WO2008060998A1 - Indole sulfonamides as sfrp-1 modulators - Google Patents
Indole sulfonamides as sfrp-1 modulators Download PDFInfo
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- WO2008060998A1 WO2008060998A1 PCT/US2007/084245 US2007084245W WO2008060998A1 WO 2008060998 A1 WO2008060998 A1 WO 2008060998A1 US 2007084245 W US2007084245 W US 2007084245W WO 2008060998 A1 WO2008060998 A1 WO 2008060998A1
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- phenylsulfonyl
- indole
- sulfonamide
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- sulfonyl
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- 0 *c1cccc2c1c(S(N*)(=O)=O)c[n]2S(=O)=O Chemical compound *c1cccc2c1c(S(N*)(=O)=O)c[n]2S(=O)=O 0.000 description 7
- IKAIFPFNQGLCHO-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCC1NS(c(c1c(C(F)(F)F)cccc11)c[n]1S(c(cc1)ccc1C(O)=O)(=O)=O)(=O)=O)=O Chemical compound CC(C)(C)OC(N(CC1)CCC1NS(c(c1c(C(F)(F)F)cccc11)c[n]1S(c(cc1)ccc1C(O)=O)(=O)=O)(=O)=O)=O IKAIFPFNQGLCHO-UHFFFAOYSA-N 0.000 description 1
- WEXUBMGYGUJFKC-UHFFFAOYSA-N CC(C)(C1)NC(C)(C)CC1NS(c(c1c(C(F)(F)F)cccc11)c[n]1S(c1ccccc1)(=O)=O)(=O)=O Chemical compound CC(C)(C1)NC(C)(C)CC1NS(c(c1c(C(F)(F)F)cccc11)c[n]1S(c1ccccc1)(=O)=O)(=O)=O WEXUBMGYGUJFKC-UHFFFAOYSA-N 0.000 description 1
- FWDDDTCYTAJNPJ-UHFFFAOYSA-N CC(C)c1c(c(S(NC2CCSCC2)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 Chemical compound CC(C)c1c(c(S(NC2CCSCC2)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 FWDDDTCYTAJNPJ-UHFFFAOYSA-N 0.000 description 1
- COOKSLHGLCYMJR-UHFFFAOYSA-N CC(C)c1c(c(S(NCC(c2cccnc2)O)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 Chemical compound CC(C)c1c(c(S(NCC(c2cccnc2)O)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 COOKSLHGLCYMJR-UHFFFAOYSA-N 0.000 description 1
- WMYAESOEAOECES-UHFFFAOYSA-N CC(C)c1c(c(S(NCc2ccccc2)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 Chemical compound CC(C)c1c(c(S(NCc2ccccc2)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 WMYAESOEAOECES-UHFFFAOYSA-N 0.000 description 1
- ROORZDYDEQNKFY-UHFFFAOYSA-N CCC(c(cc1)c[n]1S(c1ccccc1)(=O)=O)=O Chemical compound CCC(c(cc1)c[n]1S(c1ccccc1)(=O)=O)=O ROORZDYDEQNKFY-UHFFFAOYSA-N 0.000 description 1
- IVCYKNLWOXRMKN-UHFFFAOYSA-N COC(c1c(c(S(NCCc(cc2)ccc2C(O)=O)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1)=O Chemical compound COC(c1c(c(S(NCCc(cc2)ccc2C(O)=O)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1)=O IVCYKNLWOXRMKN-UHFFFAOYSA-N 0.000 description 1
- RZESQBYRUAHQNU-UHFFFAOYSA-N COc1ccc(CN(C(CC2)CCC22OCCO2)S(c(c2c(C(F)(F)F)cccc22)c[n]2S(c2ccccc2)(=O)=O)(=O)=O)c(OC)c1 Chemical compound COc1ccc(CN(C(CC2)CCC22OCCO2)S(c(c2c(C(F)(F)F)cccc22)c[n]2S(c2ccccc2)(=O)=O)(=O)=O)c(OC)c1 RZESQBYRUAHQNU-UHFFFAOYSA-N 0.000 description 1
- HUCGQCCFVBHBHD-UHFFFAOYSA-N Cc1c(c(S(NCCc2ccncc2)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 Chemical compound Cc1c(c(S(NCCc2ccncc2)(=O)=O)c[n]2S(c3ccccc3)(=O)=O)c2ccc1 HUCGQCCFVBHBHD-UHFFFAOYSA-N 0.000 description 1
- XJEZOLIQBCAFQP-UHFFFAOYSA-N Cc1c(cc[n]2/S(/c3ccccc3)=[O]\C)c2ccc1 Chemical compound Cc1c(cc[n]2/S(/c3ccccc3)=[O]\C)c2ccc1 XJEZOLIQBCAFQP-UHFFFAOYSA-N 0.000 description 1
- KCYXMLWMPURRSL-UHFFFAOYSA-N O=S(c(c(c1ccc2)c2Br)c[n]1S(c1ccccc1)(=O)=O)(NC1CCNCC1)=O Chemical compound O=S(c(c(c1ccc2)c2Br)c[n]1S(c1ccccc1)(=O)=O)(NC1CCNCC1)=O KCYXMLWMPURRSL-UHFFFAOYSA-N 0.000 description 1
- VDKZHOJHVOQQSS-UHFFFAOYSA-N O=S(c(c(c1ccc2)c2Cl)c[n]1S(C1=CC=CCC1)(=O)=O)(NCCc1cccnc1)=O Chemical compound O=S(c(c(c1ccc2)c2Cl)c[n]1S(C1=CC=CCC1)(=O)=O)(NCCc1cccnc1)=O VDKZHOJHVOQQSS-UHFFFAOYSA-N 0.000 description 1
- MMIAEJBATYOSGX-UHFFFAOYSA-N O=S(c(c1c(C(F)(F)F)cccc11)c[n]1S(c1ccccc1)(=O)=O)(NC(CC1)CCC11OCCO1)=O Chemical compound O=S(c(c1c(C(F)(F)F)cccc11)c[n]1S(c1ccccc1)(=O)=O)(NC(CC1)CCC11OCCO1)=O MMIAEJBATYOSGX-UHFFFAOYSA-N 0.000 description 1
- IGUZMSNKGMXJFH-UHFFFAOYSA-N O=S(c(c1c(C(F)(F)F)cccc11)c[n]1S(c1ccccc1)(=O)=O)(NCCc1nc(cccc2)c2[nH]1)=O Chemical compound O=S(c(c1c(C(F)(F)F)cccc11)c[n]1S(c1ccccc1)(=O)=O)(NCCc1nc(cccc2)c2[nH]1)=O IGUZMSNKGMXJFH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel indole sulfonamides that act, for example, as modulators of secreted frizzled-related protein-1.
- the present invention also relates to processes for the preparation of indole sulfonamides and to their use in treating various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- Bone remodeling the process by which the adult human skeleton is continuously renewed, is carried out by osteoclasts and osteoblasts, two specialized cell types that originate from hematopoietic and mesenchymal progenitors of the bone marrow, respectively.
- a continuous and orderly supply of these cells is believed to be essential for skeletal homeostasis, as increased or decreased production of osteoclasts or osteoblasts and/or changes in the rate of their apoptosis are largely responsible for the imbalance between bone resorption and formation that underlies several systemic or localized bone diseases.
- enhanced osteoclast activity has been found to play a major role in the pathogenesis of postmenopausal osteoporosis, Paget's disease, lytic bone metastases, multiple myeloma, hyperparathyroidism, rheumatoid arthritis, periodontitis, and hypercalcemia of malignancy.
- Wnt proteins have been identified as a family of growth factors consisting of more than a dozen structurally related molecules that are involved in the regulation of fundamental biological processes such as apoptosis, adipogenesis, embryogenesis, organogenesis, morphogenesis and tumorigenesis (Nusse and Varmus, Cell 1992, 69:1073-1087).
- Wnt polypeptides are multipotent factors and have biological activities similar to those of other secretory proteins such as transforming growth factor (TGF)- ⁇ , fibroblast growth factors (FGFs), nerve growth factor (NGF), and bone morphogenetic proteins (BMPs).
- TGF transforming growth factor
- FGFs fibroblast growth factors
- NGF nerve growth factor
- BMPs bone morphogenetic proteins
- Frizzled proteins contain an amino terminal signal sequence for secretion, a cysteine-rich domain (CRD) that is thought to bind Wnt, seven putative transmembrane domains that resemble a G-protein coupled receptor, and a cytoplasmic carboxyl terminus.
- CCD cysteine-rich domain
- LDL low-density lipoprotein
- LRP low-density lipoprotein receptor-related proteins
- the first secreted frizzled-related protein was named "Frzb” (for "frizzled motif in bone development") and was purified and cloned from bovine articular cartilage extracts based on its ability to stimulate in vivo chondrogenic activity in rats (Hoang et al, J. Biol. Chem. 1996, 271 :26131-26137; Jones & Jomary, Bioessays 2002, 24:81 1-820).
- the human homologue of the bovine gene has also been cloned. Unlike the frizzled proteins, however, Frzb does not contain a serpentine transmembrane domain, and appears to be a secreted receptor for Wnt.
- Frzb cDNA encodes a 325 amino acid/36,000 dalton protein and is predominantly expressed in the appendicular skeleton.
- the highest level of expression is in developing long bones and corresponds to epiphyseal chondroblasts; expression declines and disappears toward the ossification center.
- SFRPs participate in apoptosis. Some SFRPs have thus been identified as "SARPs" for secreted apoptosis related proteins. Additional members of the SFRP family have been identified, and have been shown to be antagonists of Wnt action. There are currently at least five known human SFRP/SARP genes: SFRP-l/FrzA/FRP-l/SARP-2, SFRP-2/SDF-5/SARP-1, SFRP-3/Frzb-l/FrzB/Fritz, SFRP-4 and SFRP-5/SARP-3 (Leimeister et al, Mechanisms of Development 1998, 75:29-42).
- SFRP- 1 Secreted frizzled related protein-1
- SFRP-I Secreted frizzled related protein-1
- bone resorption disorders such as osteoporosis
- other diseases and disorders such as arthritis, chronic obstructive pulmonary disease, cartilage defects, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- the present invention relates to certain indole sulfonamides and to their use, for example, in medical treatment.
- the invention relates to indole sulfonamides that act as modulators of secreted frizzled related protein- 1.
- the compounds can be used, for example, to treat various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- the present invention is directed to compounds of Formula (I):
- R 1 is alkyl, perfluoroalkyl, halo, cyano, or COialkyl
- R 2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl
- R 3 is optionally substituted aryl.
- the present invention is directed to compounds of Formula (H).
- R 4 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl
- R 5 is hydrogen or alkyl
- R 6 is optionally substituted aryl or heteroaryl
- R 7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl, and
- X is absent or SO 2 .
- the invention relates to compositions comprising at least one compound of Formula I or II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers.
- the present invention also provides methods for treating patients suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof, that comprise administering to the patients a therapeutically effective amount of at least one compound of Formula I or II.
- autoimmune inflammatory disorders such as Graves ophthalmopathy
- alkyl refers to an optionally substituted saturated aliphatic hydrocarbon chain having 1 to 12 carbon atoms (C M2 alkyl), preferably 1 to 8 carbon atoms (Ci- 8 alkyl), more preferably 1 to 6 carbon atoms (Ci-6 alkyl), and even more preferably 1 to 3 carbon atoms (C 1 . 3 alkyl).
- C M2 alkyl preferably 1 to 8 carbon atoms
- Si-6 alkyl more preferably 1 to 6 carbon atoms
- C 1 . 3 alkyl carbon atoms
- alkyl includes straight and branched chains. In one embodiment straight chain alkyl groups have 1 to 8 carbon atoms and branched chain alkyl groups have 3 to 12 carbon atoms.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl groups.
- perfluoroalkyl refers to an optionally substituted straight or branched saturated aliphatic hydrocarbon chain of 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, in which all hydrogens are replaced with fluorine.
- alkylcarbonyl refers to the group -C(O)R' where R' is an alkyl group as previously defined.
- alkylaminothiocarbonyl refers to the group - C(S)NHR' where R' is an alkyl group as previously defined.
- carboxyalkylcarbonyl refers to the group -C(O)RX(O)OH where R' is an alkyl group as previously defined.
- cycloalkyl refers to an optionally substituted hydrocarbon ring containing 3 to 12 carbon atoms (C3-12 cycloalkyl), preferably 3 to 6 carbon atoms (C 3 . 6 cycloalkyl). Cycloalkyl groups may be monocyclic, bicyclic, or bridged, and may be saturated or partially unsaturated. "Bridged" cycloalkyl groups contain at least one carbon- carbon bond between two non-adjacent carbon atoms of the cycloalkyl ring.
- heterocycloalkyl refers to a 3 to 12 membered, and more preferably a 5 to 7 membered, optionally substituted heterocyclic ring system comprising one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur, including sulfoxide and sulfonyl.
- the heterocycloalkyl group may be saturated or partially unsaturated, and may be monocyclic, bicyclic or bridged.
- Bicyclic heterocycloalkyl groups include a monocytic heterocycloalkyl ring fused to a monocyclic heterocycloalkyl ring, a cycloalkyl ring, an aryl ring, or a heteroaryl ring.
- “Bridged” heterocycloalkyl groups contain at least one carbon- carbon bond between non-adjacent carbon atoms of the heterocycloalkyl ring.
- the term “spiroheterocycloalkyl,” as used herein, refers to two optionally substituted heterocycloalkyl groups, or one optionally substituted cycloalkyl group and one optionally substituted heterocycloalkyl group, as previously defined, that are joined by a single sp3 carbon atom that is the only common member of the two joined rings.
- alkoxy refers to the group -O-R' where R' is an alkyl group as previously defined.
- the alkoxy groups have 1 to 6 carbon atoms (Cj. 6 alkoxy).
- alkoxycarbonyl refers to the group -C(O)OR' where R' is an alkyl group as previously defined.
- alkoxycarbonylamino refers to the group -N(H)- C(O)-OR' where R' is an alkyl group as previously defined.
- alkoxycarbonylcarbonyl refers to the group - C(O)C(O)OR' where R' is an alkyl group as previously defined.
- alkoxycarbonylalkylaminothiocarbonyl refers to the group -C(S)-NH-R' -C(O)-OR' where R' is an alkyl group as previously defined.
- hydroxycarbonylcarbonyl refers to the group - C(O)C(O)OH.
- aryl refers to an optionally substituted carbocyclic aromatic ring e.g. having 6 to 14 ring carbon atoms (C ⁇ - ⁇ aryl), preferably 6 to 10 ring carbon atoms (Ce-io aryO- Aryl groups may be monocyclic or bicyclic. Exemplary aryl groups include phenyl and naphthyl.
- arylalkyl refers to the group -R'-aryl where aryl is an aryl group as previously defined, and R' is an alkyl group as previously defined.
- arylcarbonyl refers to the group -C(O)-aryl, where aryl is an aryl group as previously defined.
- alkoxycarbonylarylcarbonyl refers to the group - C(O)-aryl-C(O)-OR' where aryl is an aryl group as previously defined and R' is an alkyl group as previously defined.
- carboxyarylaminothiocarbonyl refers to the group - C(S)-NH-aryl-C(O)OH where aryl is an aryl group as previously defined.
- arylaminothiocarbonyl refers to the group -C(S)NH(aryl), where aryl is an aryl group as previously defined.
- arylsulfonyl refers to the group -S(O)2-aryl where aryl is an aryl group as previously defined.
- cyanoarylcarbonyl refers to the group -C(O)-aryl-CN where aryl is an aryl group as previously defined.
- alkylarylcarbonyl refers to the group -C(O)-aryl-R' where R' is an alkyl group as previously defined and aryl is an aryl group as previously defined.
- carboxyarylcarbonyl refers to the group -C(O)-aryl- C(O)OH where aryl is an aryl group as previously defined.
- carboxyarylsulfonyl refers to the group -S ⁇ 2 -aryl- C(O)OH where aryl is an aryl group as previously defined.
- heteroaryl refers to an optionally substituted 5 to 10 membered monocyclic or bicyclic carbon containing aromatic ring having 1 to 3 of its ring members independently selected from nitrogen, sulfur and oxygen.
- monocyclic rings preferably have 5 to 6 ring members, and bicyclic rings preferably have 8 to 10 ring members.
- heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, and quinazolinyl.
- halogen or halo, refer to chlorine, bromine, fluorine or iodine.
- nitro refers to -NO 2 .
- sulfonyl refers to -SO 2 -.
- sulfoxide refers to -SO-.
- substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, alkyl, perfluoroallcyl, alkyamino, diaikylamino, alkoxy, alkylcarbonyl, arylcarbonyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, haloalkyl, perfluoroalkylalkyl, alkenyl, alkynyl, arylalkyl and the like.
- Substituent groups that have one or more available hydrogen atoms can in turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions.
- the term "optionally substituted aryl” is intended to mean an aryl group that can optionaly have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the aryl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).
- impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
- impermissible substitution patterns are well known to the skilled artisan
- protecting group with respect to amine groups, hydroxyl groups and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art, such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
- Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxy methyl ether, 2- methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
- a reagent such as, but not limited
- Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB, benzyl, and dithiosuccinimide; and others.
- Examples of protected or capped sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
- activated or “an activating group” or “R A " as used herein indicates having an electrophilic moiety bound to a substituent, capable of being displaced by a nucleophile.
- activating groups are halogens, such as Cl 3 Br or I, and F; triflate; mesylate, or tosylate; esters; aldehydes; ketones; epoxides; and the like.
- An example of an activated group is acetylchloride, which is readily attacked by a nucleophile, such as piperidine group to form a N-acetylpiperidine functionality.
- deprotecting refers to removal of a protecting group, such as removal of a benzyl or BOC group bound to an amine. Deprotecting may be preformed by heating and/or addition of reagents capable of removing protecting groups. One preferred method of removing BOC groups from amino groups is to add HCl in ethyl acetate. Many deprotecting reactions are well known in the art and are described in Protective Groups in Organic Synthesis, Greene, T. W., John Wiley & Sons, New York, NY, (1st Edition, 1981).
- terapéuticaally effective amount refers to the amount of a compound of Formula 1 or II that, when administered to a patient, is effective to at least partially treat a condition from which the patient is suffering or is suspected to suffer. Such conditions include, but are not limited to, osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, and leiomyoma.
- pharmaceutically acceptable salts or “pharmaceutically acceptable salt” includes acid addition salts, namely salts derived from treating a compound of formula I or II with an organic or inorganic acids or bases. Where the compound having formula I or II has an acidic function, the term “pharmaceutically acceptable salts” or “pharmaceutically acceptable salt” includes salts derived from bases, for instance, sodium salts.
- patient refers to a mammal.
- administer refers to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.
- treat refers to partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
- shocker and “suffering,” as used herein, refer to one or more conditions with which a patient has been diagnosed, or is suspected to have.
- R 1 is alkyl, perfluoroalkyl, halo, cyano, or CCt ⁇ lkyl;
- R 2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl
- R 3 is optionally substituted aryl.
- the aryl, alkyl, cycloalkyl, heterocycloalkyl, and spiroheterocycloalkyl groups found in compounds of Formula I are optionally substituted with one or more substituents that include, for example, hydrogen, branched and unbranched alkyl, perfluoroalkyl, bromo, chloro, fiuoro, iodo, cyano, CO 2 alkyl, CO2H, phenyl, hydroxy, alkoxy, perfluoroalkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, and diarylamino.
- substituents include, for example, hydrogen, branched and unbranched alkyl, perfluoroalkyl, bromo, chloro, fiuoro, iodo, cyano, CO 2 alkyl, CO2H, phenyl, hydroxy, alkoxy, perfluoroalkoxy, aryloxy, amino
- the aryl, alkyl, cycloalkyl, heterocycloalkyl, and spiroheterocycloalkyl groups found in compounds of Formula I are optionally substituted with 1-3 substituents selected from hydrogen, Ci-C 6 alkyl, Ci-C 6 perfluoroalkyl, halo, cyano, CO 2 -(Ci-Ce) alkyl, CO 2 H, phenyl, hydroxy, Ci-C ⁇ alkoxy, Ci-Ce perfluoroalkoxy, C6-C10 aryloxy, amino, Ci-C ⁇ alkylamino, di(Ci-C6)alkylamino, C 6 -C 10 arylamino, and di(C6-Cio)arylamino.
- substituents selected from hydrogen, Ci-C 6 alkyl, Ci-C 6 perfluoroalkyl, halo, cyano, CO 2 -(Ci-Ce) alkyl, CO 2 H, pheny
- R 1 of Formula I is C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl, halo, cyano, or CO 2 C 1 -C3 alkyl.
- R 1 is methyl, ethyl, isopropyl, trifluoromethyl, bromo, chloro, cyano, or C ⁇ 2methyl.
- R 1 is trifluoromethyl, isopropyl, or bromo.
- R 2 is C 1 -C 3 alkyl, substituted C 1 -Cs alkyl, cyclohexyl, substituted cyclohexyl, piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, substituted tetrahydrothiopyranyl, or 1,4- di oxaspi rodecany 1.
- the substituents for the piperidinyl groups of R 2 of Formula I are selected from alkyl, alkoxycarbonyl, substituted alkylcarbonyl, substituted arylcarbonyl, substituted arylsulfonyl, alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, substituted arylaminothiocarbonyl, and substituted alkylaminothiocarbonyl.
- the piperidinyl group substituents are selected from alkyl, alkoxycarbonyl, carboxyalkylcarbonyl, cyanoarylcarbonyl, alkylarylcarbonyl, carboxyarylcarbonyl, alkoxycarbonylarylcarbonyl, carboxyarylsulfonyl, alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, carboxyarylaminothiocarbonyl, and alkoxycarbonylalkylaminothiocarbonyl.
- the piperidinyl group substituents are selected from methyl, ethoxycarbonyl, tertbutyloxycarbonyl, carboxypropylcarbonyl, methoxycarbonylphenylcarbonyl, carboxyphenylcarbonyl, cyanophenylcarbonyl, tertbutylphenylcarbonyl, carboxyphenylsulfonyl, methoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, carboxyphenylaminothiocarbonyl, and methoxycarbonylmethyleneaminothiocarbonyl.
- the substituents for the alky groups of R 2 of Formula I are selected from alkoxy, heterocycloalkyl, aryl, substituted aryl, heteroaryl, cyano, hydroxyl, and hydroxy sulfonyl.
- the alkyl group substituents are selected from methoxy, morpholinyl, piperidinyl, thiomorpholinyl, tetrahydropyranyl, phenyl, carboxyphenyl, pyridyl, imidazolyl, benzoimidazolyl, cyano, hydroxyl, and hydroxy sulfonyl.
- the substituents for the cyclohexyl groups of R 2 of Formula I are selected from hydroxyl, oxo, and alkyloxycarbonylamino.
- the cyclohexyl group substituents are selected from hydroxyl, oxo, and tertbutyloxycarbonylamino.
- the substituents for the tetrahydrofuranyl and tetrahydrothiopyranyl groups of R 2 of Formula I are oxo groups.
- the substituents for the pyrrolidinyl groups of R 2 of Formula I are arylalkyl groups, preferably phenylmethyl groups.
- R 3 is phenyl or substituted phenyl.
- R 3 is phenyl.
- R 1 is methyl, ethyl, isopropyl, trifluoromethyl, bromo, chloro, cyano, or C ⁇ 2 methyl
- R 2 is C1-C3 alkyl, substituted C 1 -C 3 alkyl, cyclohexyl, substituted cyclohexyl, piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, substituted tetrahydrothiopyranyl, or 1,4- dioxaspirodecanyl; and R 3 is phenyl or substituted phenyl.
- representative compounds of Formula I include: l-CphenylsulfonyO-N-piperidin ⁇ -yl- ⁇ Ctrifluoromethy ⁇ -lH-indole-S-sulfonamide;
- Preferred compounds of Formula I include: l-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH-indole-3-sulfonamide;
- R 4 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl
- R 5 is hydrogen or alkyl
- R 6 is optionally substituted aryl or heteroaryl
- R 7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl
- X is absent or SO2.
- the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups present in compounds of Formula II are optionally substituted with one or more substituents that include, for example, halogen, CN, OH, NO 2 , amino, -alkylamino, -dialkylamino, alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, C 1 to Cs alkoxy, Ci to C 3 perfluoroalkyl, Ci to C 3 perfluoroalkoxy, -0-(CH 2 )o- 3 -aryl, -S-(CH 2 )o- 3 -aryl, alkyl carbonyl, including -CO-(Ci to C 6 alkyl) and -CO-(Ci to C 6 substituted alkyl), -CO-(CH 2 )o- 3 -aryl, -SO 2 -(
- alkylcarboxy including -COO-(Ci to C 6 alkyl) and -COO-(Ci to C 6 substituted alkyl), -COO-(CH 2 )o- 3 -aryl, and -CON(R 5 )Z.
- X of Formula II is SO 2 . In other embodiments, X is absent.
- R 4 is optionally substituted cycloalkyl, or heterocycloalkyl.
- R 4 is optionally substituted heterocycloalkyl, and in particularly preferred embodiments, R 4 is optionally substituted piperidinyl.
- the optional substituents for the alkyl, cycloalkyl, and heterocycloalkyl groups of R 4 of Formula II are selected from alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl , dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkyl, perfluoroalkyl,
- the optional substituents for the alkyl, cycloalkyl, and heterocycloalkyl groups of R 1 are preferably tertbutyloxy, trifluoromethylcarbonyl, tertbutyloxycarbonyl, trifluoromethylsulfonyl, dimethylaminosulfonyl, or carboxyphenylsulfonyl.
- R 5 is hydrogen, methyl, ethyl, propyl, or isopropyl.
- R 5 is preferably hydrogen or methyl.
- Still further embodiments of the invention relate to compounds of Formula ⁇ in which R 6 is aryl and X is either sulfonyl or is absent.
- R 6 is phenyl and X is either sulfonyl or is absent.
- R 7 is C1-C 3 alkyl, C1-C3 perfluoroalkyl, halo, cyano, or CO2C1-C3 alkyl.
- R 7 is methyl, ethyl, isopropyl, trifiuoromethyl, bromo, chloro, cyano, Or COaCH 3 .
- R 7 is trifiuoromethyl.
- Certain embodiments of the invention are directed to compounds of Formula II in which R 1 is optionally substituted heterocycloalkyl; R 2 is hydrogen, methyl, ethyl, or propyl; R 3 is phenyl; and R 4 is methyl, ethyl, isopropyl, trifiuoromethyl, bromo, chloro, cyano, or CO 2 CH 3 .
- Compounds of Formula 1 and Il may be used to modulate the activity of secreted frizzled related protein-1.
- Such compounds are of interest for the treatment of osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- the present invention therefore provides methods of treating, preventing, inhibiting, or alleviating each of the maladies listed above in a mammal, preferably in a human, comprising administering a therapeutically effective amount of a compound of Formula I or II or a pharmaceutically acceptable salt thereof to a patient suspected to suffer from such a malady.
- the invention relates to compositions comprising at least one compound of Formula I or II, or a steroisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
- Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the bone.
- the compositions comprise mixtures of one or more compounds of Formula I or II.
- Certain of the compounds of Formula I and II contain stereogenic carbon atoms or other chiral elements and thus give rise to stereoisomers, including enantiomers and diastereomers.
- the invention generally relates to all stereoisomers of the compounds of Formula I or IT, as well as to mixtures of the stereoisomers.
- An enantiomer can, in some embodiments of the invention, be provided substantially free of the corresponding enantiomer.
- reference to an enantiomer as being substantially free of the corresponding enantiomer indicates that it is isolated or separated via separation techniques or prepared so as to be substantially free of the corresponding enantiomer.
- substantially free means that a significantly lesser proportion of the corresponding enantiomer is present. In preferred embodiments, less than about 90 % by weight of the corresponding enantiomer is present relative to desired enantiomer, more preferably less than about 1% by weight.
- Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or preferred enantiomers, can be prepared by methods described herein. Methods for the preparation of enantiomers are described, for example, in Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et ai, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H.
- Another aspect of the invention provides a process for the preparation of a compound of formula (I):
- R 1 is alkyl, perfluoroalkyl, halo, cyano, or CO ⁇ alkyl
- R 2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl
- R 3 is optionally substituted aryl; the process comprising: contacting H 2 N-R 2 with a compound of formula IA:
- the compound of formula IA is prepared by: contacting chlorosulfonic acid with a compound of formula IB:
- the process further comprises reacting the chlorosulfonic acid contacted compound of formula IB with PCI5.
- the compound of formula IB is prepared by: contacting R 3 -SCh-Cl with a compound of formula IC:
- the compound of formula IC is synthesized by:
- the reducing metal is iron and the acid is acetic acid.
- Another aspect of the invention provides a process for the preparation of a compound of formula IIA:
- R 4 is optionally substituted alkyl, cycloalkyl, or heterocycioalkyl
- R 6 is optionally substituted aryl or heteroaryl
- R 7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl
- X is absent or SO 2 ;
- Another embodiment comprises contacting the compound of formula HA with a compound of formula: R A -R 5 , to form a compound of formula II:
- R A is an activating group
- R 5 is alkyl or substituted alkyl. a more particular embodiment thereof, R A is Cl, Br, I, tosylate, mesylate, triflate, an ester, an epoxide or an aldehyde.
- the compound of formula HA is prepared by: contacting sulfonyl chloride with a compound of formula 1IC: lie.
- the process further comprises reacting the sulfonyl chloride contacted compound of formula UC with PCI5.
- the compound of formula IIC is prepared by: contacting vinylmagnesium bromide with a compound of formula TID:
- the compound of formula IID is prepared by: contacting R B -X-R 6 with a compound of formula HE:
- hal is halogen; and if X is SO 2 then R B is hydrogen or if X is absent then R B is a boronic acid.
- a 4-substituted indole 1 is treated sequentially with an appropriate base, such as sodium hydride, in an appropriate solvent, such as DMF or THF, and then a sulfonyl chloride, such as benzenesulfonyl chloride, to produce the corresponding N- sulfonyl indole 2.
- an appropriate base such as sodium hydride
- an appropriate solvent such as DMF or THF
- the N-sulfonyl indole 2 can then be sulfonylated with an appropriate sulfonating agent, such as chlorosulfonic acid or sulfuric acid, in the presence or absence of a suitable solvent, such as dichloromethane or chloroform, to produce either the indole 3-sulfonyl chloride 3 directly or the indole 3-sulfonic acid which can be converted to the indole 3-sulfonyl chloride 3 by treatment with an appropriate chlorinating agent, such as phosphorous pentachloride in phosphorous oxychloride.
- an appropriate chlorinating agent such as phosphorous pentachloride in phosphorous oxychloride.
- the indole 3-sulfonyl chloride 3 can then be condensed with various primary or secondary amines in the presence of a base, such as pyridine or triethylamine, in a suitable solvent, such as dichloromethane or DMF, to provide the target compound 4.
- a base such as pyridine or triethylamine
- a suitable solvent such as dichloromethane or DMF
- the nitrogen-protecting group can be cleaved by standard deprotection chemistry, such as cleavage of the 2,4- dimethoxybenzyl group under acidic conditions.
- an amine containing a carbonyl protecting group such as an acetal or ketal
- this protecting group can be removed by standard deprotection chemistry.
- an amine containing an ester group is utilized, the ester group could be hydrolyzed to its corresponding acid or reduced to its corresponding alcohol by standard techniques.
- the targets are prepared from 4a or 4b as shown in Scheme 2.
- a suitable acid such as trifluoroacetic acid
- Compound 4c can also be treated with a carboxylic acid in the presence of activating agents, such as dicyclohexylcarbodiimide and dimethylaminopyridine, with a base, such as triethylamine or pyridine, to provide the corresponding amides.
- activating agents such as dicyclohexylcarbodiimide and dimethylaminopyridine
- base such as triethylamine or pyridine
- compound 4a can be used to prepare a variety of substitutions at the R 3 position as shown in Scheme 3.
- a suitable base such as potassium hydroxide
- a suitable solvent such as methanol
- Indole 4e can be treated sequentially with an appropriate base, such as sodium hydride, in an appropriate solvent, such as DMF or THF, and then a sulfonyl chloride, such as a substituted benzenesulfonyl chloride, to produce the corresponding N-sulfonyl indole 4a.
- This differentially substituted indole can be further manipulated as described in Scheme 2.
- the resulting target compound 4f can be treated with an appropriate oxidizing agent, such as oxone or meta-chloroperoxybenzoic acid, to produce the sulfoxide 4g as shown in Scheme 4.
- an appropriate oxidizing agent such as oxone or meta-chloroperoxybenzoic acid
- the sulfoxide diasteroemers 4g can be separated or they can be further oxidized to the sulfone 4h.
- the thiopyran 4f can be converted directly to the sulfone 4h by the addition of excess oxidizing agent.
- an appropriately substituted nitrobenzene A such as 4- chloro-3-nitrobenzotrifluoride or 4-bromo-3-nitrobenzotrifluoride
- an appropriate sulfinic acid salt such as benzene sulfinic acid sodium salt
- a suitable solvent such as dimethylsulfoxide
- an appropriately substituted nitrobenzene A such as 4-chloro-3-nitrobenzotrifluoride or 4-bromo-3-nitrobenzotrifluoride
- an appropriately substituted aromatic compound such as an arylboronic acid or aryl stannane
- X a covalent bond
- a suitable solvent such as THF
- an aqueous acid such as saturated ammonium chloride
- indole C can be treated with a base, such as sodium hydride, in an appropriate solvent, such as DMF, and then treated with an electrophile, such as iodomethane, to provide substituted indoles D.
- a base such as sodium hydride
- an appropriate solvent such as DMF
- an electrophile such as iodomethane
- Indoles C or D can be treated with a sulfonylating agent, such as chlorosulfonic acid, in a suitable solvent, such as dichloromethane, or in the absence of solvent to produce the sulfonyl chlorides E.
- the sulfonyl chlorides E can be treated with amines in the presence of a base, such as triethylamine or diisopropylethylamine, in an appropriate solvent, such as dimethylformamide or dichloromethane, to generate the target molecules.
- a base such as triethylamine or diisopropylethylamine
- an appropriate solvent such as dimethylformamide or dichloromethane
- the targets are prepared from F.I as shown in Scheme 8.
- a suitable acid such as trifluoroacetic acid
- G treatment of G with an appropriate electrophile, such as an acid chloride, acid anhydride, sulfonyl chloride, isocyanate, or isothiocyanate in the presence of a base, such as triethylamine or pyridine, provides the target compounds H.
- an appropriate electrophile such as an acid chloride, acid anhydride, sulfonyl chloride, isocyanate, or isothiocyanate in the presence of a base, such as triethylamine or pyridine
- Compound G can also be treated with a carboxylic acid in the presence of activating agents, such as dicyclohexylcarbodiimide and dimethylaminopyridine, with a base, such as triethylamine or pyridine, to provide the corresponding amides H.
- activating agents such as dicyclohexylcarbodiimide and dimethylaminopyridine
- base such as triethylamine or pyridine
- the invention relates to compositions comprising at least one compound of Formula I or II, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
- Such compositions are prepared in accordance with general pharmaceutical formulation procedures, such as, for example, those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety.
- Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.
- the compounds of Formula I and II can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers.
- Applicable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials.
- the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99 % of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat.
- the liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils ⁇ e.g. fractionated coconut oil and arachis oil
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
- the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
- Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
- Compositions for oral administration can be in either liquid or solid form.
- the compounds of Formula ⁇ and II can be administered rectally or vaginally in the form of a conventional suppository.
- the compounds of Formula I and II can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
- the compounds of Formula I and II can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
- the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
- the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
- Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable.
- a variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- the amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like.
- compounds of Formula I or II are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
- An amount adequate to accomplish this is defined as a "therapeutically effective amount.”
- the dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician.
- the variables involved include the specific condition and the size, age, and response pattern of the patient.
- the compounds can be administered orally, rectally, parenterally, or topically to the skin and mucosa.
- the usual daily dose depends on the specific compound, method of treatment and condition treated.
- the usual daily dose is 0.01 - 1000 mg/kg for oral application, preferably 0.5 - 500 mg/kg, and 0.1 - 100 mg/kg for parenteral application, preferably 0.5 - 50 mg/kg.
- the present invention is directed to prodrugs of compounds of Formula I and II.
- prodrug means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I and II.
- Various forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed).
- Step 4 l-BenzenesulfonyM-trifluoromethyl-lH-indole-S-sulfonic acid
- Step 8 l-BenzenesulfonyM-trifluoromethyl-lH-indole-S-sulfonic acid piperidin-4- ylamide hydrochloric acid
- Example 2 As in Example 2, l-benzenesulfonyM-trifluoromethyl-lH-indole ⁇ -sulfonic acid piperidin-4-ylamide hydrochloride (250 mg, 0.51 mmol) from Example 1, Step 8, terephthalic acid monomethyl ester chloride (112 mg, 0.56 mmol), and diisopropylethylamine (250 ⁇ L, 1.8 mmol) in dichloromethane (5.0 mL) provided methyl 4- ⁇ [4-( ⁇ [l-(phenylsulfonyl)- 4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl ⁇ amino)piperidin-l-yl]carbonyl ⁇ benzoate (260 mg).
- Example 2 As in Example 2, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonic acid piperidin-4-ylamide hydrochloride (110 mg, 0.21 mmol) from Example 1, Step 8, methyl 2- isothiocyanatoacetate (28 mg, 0.21 mmol), and diisopropylethylamine (55 ⁇ L, 0.31 mmol) in dichloromethane (5.0 mL) provided methyl N- ⁇ [4-( ⁇ [l-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indol-3- yl]sulfonyl ⁇ amino)piperidin-l-yl]carbonothioyl ⁇ glycinate (29 mg).
- Example 1 As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (200 mg, 0.47 mmol) from Example 1, Step 5, alpha-amino-gama- butyrolactone hydrobromide (84 mg, 0.47 mmol), and diisopropylethylamine (247 ⁇ L, 1.4 mmol) in dichloromethane (5.0 mL) provided N-(2-oxotetrahydrofuran-3-yl)-l-(phenylsulfonyl)- 4-(trifluoromethyl)-lH-indole- 3-sulfonamide (101 mg).
- Example 2 As in Example 2, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonic acid piperidin-4-ylamide hydrochloride (150 mg, 0.31 mmol) from Example 1, Step 8, glutaric anhydride (39 mg, 0.34 mmol), and diisopropylethylamine (60 ⁇ L, 0.43 mmol) in dichloromethane (6.0 mL) provided 5-oxo-5-[4-( ⁇ [l-(phenylsulfonyl)-4-(trifiuoromethyl)-lH- indol-3- yl]sulfonyl ⁇ amino)piperidin-l-yl]pentanoic acid (91 mg).
- Example 8 4-[2-( ⁇ [l-(PhenylsulfonyI)-4-(trifluoroinethyl)-lH-indol-3- yl]s ⁇ lfonyl ⁇ amino)etliyl]be ⁇ izoic acid
- Step 1 tert-Butyl [trans-4-( ⁇ [l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl ⁇ amino)cyclohexyl]carbamate
- Step 2 N-(2,4-dimethoxybenzyl)-l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4- yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide
- Step 7 l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (500 mg, 1.2 mmol) from Example 1, Step 5, N-(2,4- dimethoxybenzyl)tetrahydro-2H-thiopyran-4-amine (630 mg, 2.4 mmol), and triethyiamine (490 uL, 3.5 mmol) in dichloromethane (25 mL) provided N-(2,4-dimetho ⁇ ybenzyl)-l- (phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yI)-4-(trifluoromethyl)-lH-indole-3-sulfonamide (720 mg).
- Step 3 l-CPhenylsulfony ⁇ -N-Ctetrahydro ⁇ H-thiopyran ⁇ -yO ⁇ tri
- N-(2,4-dimethoxybenzyl)-l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)- 4-(trifluoromethyl)-lH-indole-3-sulfonamide (720 mg, 1.1 mmol) was dissolved in 6% trifluoroacetic acid/dichloromethane (6 mL) and stirred overnight at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted.
- Example 12 cis. cis-N-(l-Oxidotetrahydro-2H-thiopyran-4-yl)-l-(pheiiylsulfonyl)-4- (trifluoromethyl)- lH-indole-3-sulfonamide
- trans-4aminocyclohexanol 110 mg, 0.94 mmol
- sodium bicarbonate 160 mg, 1.9 mmol
- l-benzenesulfonyl-4- trifluoromethyl-lH-indole-3-sulfonyl chloride 400 mg, 0.94 mmol
- acetonitrile 5 mL
- Step 2 N-(2,4-Dimethoxybenzyl)-l-(phenylsulfonyl)-N-(l,4-dioxaspiro[4.5]decan-8- yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide
- N-(2,4-dimethoxyben;.yl)-l-(phenylsulfonyl)-N-(l,4-dioxaspiro[4.5]decan-8- yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide 500 mg, 0.72 mmol was dissolved in 20% trifluoroacetic acid/dichloromethane (20 mL) and stirred for two days at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted.
- Example 1 As in Example 1, Step 7, l-benzenesulfonyl-4-trifiuoromethyl-lH-indole-3- sulfonyl chloride (175 mg, 0.41 mmol) from Example 1, Step 5, 3-(2-aminoethyl)pyridine (55 mg, 0.45 mmol), and diisopropylethylamine (144 ⁇ L, 1.0 mmol) in dichloromethane (10 mL) provided l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide (35 mg).
- Example 2 As in Example 2, l-benzenesulfonyM-trifluoromethyl-lH-indole-S-sulfonic acid piperidin-4-ylamide hydrochloride (325 mg, 0.62 mmol) from Example 1, Step 8, methyl chlorooxoacetate (91 mg, 0.74 mmol), and diisopropylethylamine (220 ⁇ L, 1.5 mmol) in dichloromethane (8.0 mL) provided methyl oxo[4-( ⁇ [l-(phenylsulfonyl)-4-(trifiuoromethyl)-lH- indol-3- yl]sulfonyl ⁇ amino)piperidin-l-yl]acetate (206 mg).
- Example 1 As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (150 mg, 0.35 mmol) from Example 1, Step 6, 4-aminotetrhydropyran hydrochloride (51 mg, 0.37 mmol), and diisopropylethylamine (148 ⁇ L, 1.1 mmol) in dichloromethane (8.0 mL) provided l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide (165 mg).
- Example 22 l-(Phenylsulfonyl)- ⁇ /-pyrroIi(lin-3-yl-4-(trifluoromethyl)-lf/-ind ⁇ le-3- sulfonamide
- Step 1 tcrt-Butyl 3-(l-(phenylsulfonyl)-4-(trifluoromcthyl)-lH-indole-3- sulfonamido)pyrrolidine-l-carboxylate
- Example 1 As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (150 mg, 0.35 mmol) from Example 1, Step 5, 4-(aminomethyl)tetrahyropyran (41 mg, 0.35 mmol), and morpholinomethyl polystyrene (700 mg, excess) in dichloromethane (5.0 mL) provided l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-4-(trifluoromethyl)- lH-indole-3-sulfonamide (64 mg).
- Example 25 l-(phenylsulfonyl)- ⁇ r -(2-pyridin-2-ylethyl)-4-(trifIuoromethyl)-ljRr-indole-3- sulfonamide
- Example 1 As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (200 mg, 0.47 mmol) from Example 1, Step 5, 2-(2-aminoethyl)pyridine (69 mg, 0.57 mmol), and triethylamine (164 ⁇ L, 1.2 mmol) in dichloromethane (4.0 mL) provided 1- (phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-4-(trifluororaethyl)-lH-indole-3-sulfonamide (45 mg).
- Step 2 4-(3-(N-(l-(tert-Butoxycarbonyl)piperidin-4-yl)sulfamoyl)-4-(trifluoromethyl)- lH-indol-l-ylsulfonyl)benzoic acid
- Step 2 4-(3-(N-(I -(tert-butoxycarbonyl)piperidin-4- yl)sulfamoyl)-4-(trifluoromethyl)-lH-indol-l-ylsulfonyl)benzoic acid (150 mg, 0.17 mmol) in hydrochloric saturated ethyl acetate (8.0 mL) at 60 0 C provided the hydrochloride salt of 4- ⁇ [3- [(piperidin-4-ylamino)sulfonyl]-4-(trifluoromethyl)-lH-indol-l-yl]sulfonyl ⁇ benzoic acid (120 mg)
- Example 30 S-tt ⁇ l-CPhenylsuIfony ⁇ -Ctri ⁇ uoroinethyl ⁇ lM-indoI-S- yljsulfonyl ⁇ amino)propa ⁇ ie-l-s ⁇ ilfoiiic acid
- Step 3 l-(l,3-Dioxan-2-yl)-4-methyl-3-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)pentan-3- ol
- Step 7 5-[4-( ⁇ [4-Isopropyl-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl ⁇ amino)piperidin-l-yl]-5-oxopentanoic acid
- Step 2 t ⁇ rf-butyl 4-( ⁇ [4-i sopropy 1-1 -(phenyl sulfony I)- IH- indol-3-yl]sulfonyl ⁇ amino)piperidine-l-carboxylate (1.9 g, 3.4 mmol) from Example 36, in hydrochloric saturated ethyl acetate (75 mL) provided the hydrochloride salt of 4-isopropyl-l- (phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (360 mg).
- Example 2 4-isopropyl-l-(phenylsulfonyI)-N-piperidin-4-yl-lH-indole-3- sulfonamide hydrochloride (300 mg, 0.60 mmol) from Example 37, 4-(chlorosulfonyl)benzoic acid (133 mg, 0.60 mmol), and triethylamine (336 ⁇ L, 12.4 mmol) in dichloromethane (6.0 mL) provided 4- ⁇ [4-( ⁇ [4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl ⁇ amino)piperidin-l- yl]sulfonyl ⁇ benzoic acid (150 mg).
- N-(2,4-dimethoxybenzyl)-l-(phenylsulfonyl)-N- (tetrahydro-2H-thiopyran-4-yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide 500 mg, 1.3 mmol
- 6 % trifiuoroacetic acid/dichloromethane (6.0 niL) provided 4-isopropyl-l- (phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)-lH-indole-3-sulfonamide (490 mg).
- Example 42 7V-(l,l-Dioxidotetrahydro-2/f-thiopyran-4-yl)-4-isopropyI-l-(phenylsulfonyl)- lH-indole-3-suIfonaniide
- Example 43 4-Isopropyl- ⁇ /-(l-oxidotetrahydro-2//-thiopyran-4-yl)-l-(phenylsuIfonyI)-l/f- indole-3-sulfonaniide
- Example 44 4-Isopropyl-l-(phenylsulfonyl)-/V-(2-pyridin-3-ylethyI)-l//-indole-3- sulfonamide
- Example 45 /V-[3-(l//-Imidazol-l-yl)propylJ-4-isopropyl-l-(phenylsulfonyl)-l/f-indole-3- suifonamide
- Example 46 4-IsopropyI-N-(2-morphoIin-4-ylethyl)-l-(phenylsulfonyl)-l//-indole-3- sulfonamide
- Example 48 4-Isopropyl-l-(phenylsuIfonyl)- ⁇ '-(tetrahydro-2//-pyran-4-yI)-lH-indole-3- sulfonamide
- Example 51 4-IsopropyI-l-(phenylsulfonyl)-N-[2-(tetrahydro-2//-pyran-4-yl)ethyl]-l//- indoIe-3-sulfonam ide
- Step 7 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (150 mg, 0.38 mmol) from Example 34, Step 6, 4-aminomethyltetrahydropyran (43 mg, 0.38 mmol), and morpholinomethyl-polystyrene (500 mg, excess) in dichloromethane (4.0 mL) 4-i sopropyl- 1 -(phenyl sulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)- lH-indole-3-sulfonamide (120 mg).
- Example 54 4-lsopropyl-N-(3-phenylpropyl)-l-(phenylsulfonyl)-lH-indole-3-suIfonamide
- Example 1 4-isopropyl-l-(phenylsulfonyl)-l ⁇ -indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, 3-phenyl-l-propylamine (36 ⁇ L, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided 4-isopropyl-N-(3-phenylpropyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (56 mg).
- Example 2 4-isopropyl-l-(phenylsulfonyl)- ⁇ f-piperidin-4-yl-lH-indole-3- sulfonamide hydrochloride (100 mg, 0.20 mmol) from Example 37, 3-carboxyphenylisocyanate (45 mg, 0.20 mmol), and triethylamine (55 ⁇ L, 0.40 mmol) in dichloromethane (4.0 mL) provided 3-( ⁇ [4-( ⁇ [4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl ⁇ amino)piperidin-l- yl]carbonothioyl ⁇ amino)benzoic acid (34 mg).
- Example 56 iV-(2-Hydroxy-2-pyridin-3-ylethyl)-4-isopropyl-l-(phenylsulfonyl)-l/ir-indole- 3-sulfonamide
- N-(2,4-Dimethoxybenzyl)-4-isopropyl-N-(l- methylpiperidin-4-yl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide 500 mg, 0.72 mmol was dissolved in 20% trifluoroacetic acid/dichloromethane (8.0 mL) to provide 4-isopropyl-N-(l- methylpiperidin-4-yl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (120 mg).
- Example 59 Methyl 4- ⁇ [4-( ⁇ [4-isopropyl-l-(phenylsulfonyl)-l//-indol-3- yl]suiro ⁇ iyl ⁇ aiiiino)piperidiii-l-yl]carboiiyl ⁇ benzoale
- Step 2 l-BenzenesulfonyM-bromo-lH-indole-S-sulfonic acid
- Step 2 tert-butyl 4-( ⁇ [4-bromo-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl ⁇ amino)piperidine-l-carboxylate (250 mg, 0.41 mmol) from Example 61, and 2.0 M hydrochloric saturated dioxane (0.5 mL) in ethanol (3 mL) provided the hydrochloride salt of 4- bromo-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (215 mg).
- Example 1 As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.23 mmol) from Example 60, Step 3, 4-aminotetrahydropyran, (23 mg, 0.23 mmol), and triethylamine (70 ⁇ L, 0.69 mmol) in dichloromethane (3.0 mL) provided 4-bromo-l- (phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide (76 mg).
- Example 65 4-Bromo-l-(phenylsulfonyl)- ⁇ '-[2-(tetrahydro-2//-pyran-4-yl)ethyl]-l//- indole-3-sulfonamide
- Example 1 As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.23 mmol) from Example 60, Step 3, 4-(2-aminoethyl)tetrahydropyran, (30 mg, 0.23 mmol), and triethylamine (70 ⁇ L, 0.69 mmol) in dichloromethane (3.0 mL) provided 4- bromo-l-(phenylsulfonyl)-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-lH-indole-3-sulfonamide (63 mg).
- Step l l-(l-(Phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one
- Step 2 1 -(phenylsulfonyl)-l H-pyrrole (3.0 g, 15 mmol), propionyl chloride (1.3 mL, 15 mmol), and aluminum chloride (2.0 g, 15 mmol) in dichloroethane (40 mL) provided l-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one (2.9 g).
- Step 2 l-(l,3-Dioxan-2-yl)-3-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)pentan-3-ol
- Step 3 l-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one ( 2.9 g, 11 mmol) and (l,3-dioxan-2ylethyl)magnesium bromide (8.0 mL, 44 mmol) in tetrahydrofuran (200 mL) provided l-(l,3-Dioxan-2-yl)-3-(l-(phenylsulfonyl)-lH-pyrrol-3- yl)pentan-3-ol (4.1 g).
- Step 4 l-(l,3-Dioxan-2-yl)-3-(l-(phenylsulfonyl)-lH- pyrrol-3-yl)pentan-3-ol (4.1 g, 11 mmol) in 6% sulfuric acid/ethanol provided 4-ethyl-l- (phenylsulfonyl)-lH-indole (1.7 g)
- Example 70 tert-Buty ⁇ 4-( ⁇ [4-ethyl-l-(phenylsulfonyl)-l//-indol-3- yl]sulfonyl ⁇ amino)piperidine-l-carbo ⁇ ylate
- Step 2 ter/-butyl 4-( ⁇ [4-ethyl-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl ⁇ amino)piperidine-l-carboxylate (250 mg, 0.41 mmol) from Example 70, and 2.0 M hydrochloric saturated dioxane (2.0 mL) in ethanol (2.0 mL) provided the hydrochloride salt of 4-ethyl-l -(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (73 mg).
- Example 72 4-Ethyl-l-(phenylsulfonyI)-N-(tetrahydro-2//-pyran-4-ylinethyl)-LH-indole-3- sulfonamide
- Example 1 As in Example 1, Step 7, 4-ethyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (175 mg, 0.46 mmol) from Example 68, Step 5, 3-(2-aminoethyl)pyridine (56 ⁇ g, 0.46 mmol), and morpholinomethyl-polystyrene (500 niL, excess) in dichloromethane (4.0 mL) provided 4-ethyl-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide (61 mg).
- Step 2 l-BenzenesulfonyM-methyl-lH-indole-S-sulfonic acid
- Example 75 4-Methyl-l-(phenylsulfonyl)-iV-(2-pyridin-2-yIethyl)-li l - r -indole-3-sulfonainide
- Example 78 4-Methyl-l-(phenylsulfonyl)-N-(tetrahydro-2//-pyran-4-ylmethyl)-l ⁇
- Step 1 l-Benzenesulfonyl-4-chloro-lH-indole
- Step 2 l-Benzenesulfonyl-4-chloro-lH-indole-3-sulfonic acid
- Step 3 l-Benzenesulfonyl-4-chloro-lH-indole-3-sulfonyl chloride
- Step 4 4-Chloro-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide
- Example 80 4-Chloro-l-(phenylsulfonyl)-N-(tetrahydro-2//-pyran-4-yl)-l//-indole-3- sulfonamide
- Example 1 As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, aminoacetonitrile hydrochloride (47 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro-N-(cyanomethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (30 mg).
- Step 1 l-(phenyIsulfonyl)-lH-indole-4-carbonitrile
- Step 2 /erf-Butyl 4-( ⁇ [4-cyano-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl ⁇ amino)piperidine-l -carboxylate (70 mg, 0.13 mmol) from Example 88, and 2.0 M hydrochloric saturated dioxane (2.0 mL) in ethanol (2.0 mL) provided the hydrochloride salt of 4-cyano-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (45 mg).
- Example 1 As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 2-(2-aminoethyl)pyridine (27 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide (39 mg).
- Example 1 As in Example 1, Step 7, 4-cya ⁇ o-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 2-methoxy ethyl amine (29 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-N-(2-morpholin-4-ylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (64 mg).
- Example 1 As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 4-(2-aminoethyl)pyridine (27 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-l-(phcnylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indolc-3-sulfonamidc (29 mg).
- Example 96 4-Chloro-l-(phenyIsuIfonyl)-/V-(2-piperidin-l-yIethyl)-li/-indole-3- sulfonamide
- Step 2 4-(Methoxycarbonyl)-l -(phenylsulfonyl)- lH-indole-3-sulfonic acid
- Step 4 4-[2-( ⁇ [4-(Methoxycarbonyl)-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl ⁇ amino)ethyl]benzoic acid
- Example 103 7-(PhenyIsulfonyl)-7V-piperidin-4-yl-4-(trifluoromethyl)-lH-indoIe-3- sulfonamide
- Example 104 T-CPhenylsuIfonylJ-N-Il-CtrifluoroacetyOpiperidin- ⁇ yll- ⁇ trifluoromethyl)- lH-indole-3-sulfonamide
- the crude product was purified by flash column chromatography through silica gel (gradient elution with 0-30% ethyl acetate-hexane) to afford T ⁇ phenylsulfony ⁇ -N-fl- ⁇ rifluoroacetyOpiperidin ⁇ -ylJ ⁇ - ⁇ rifluoromethy ⁇ -lH-indole-S- sulfonamide.
- Example 104 7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)- lH-indole-3-sulfonamide, hydrochloride salt (0.10 g, 0.19 mmol), 2,2-dimethylpropionyl chloride (26 ⁇ L, 0.21 mmol) and diisopropylethylamine (73 ⁇ L, 0.42 mmol) in dichloromethane (5 mL) provided N-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]-7-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide.
- Example 106 N- ⁇ l-[(DimethyIamino)sulfonylJpiperidin-4-yl ⁇ -7-(phenylsuIfonyl)-4- (trifluoromethyl)-lH-indole-3-suIfonamide
- Example 104 7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)- lH-indole-3-sulfonamide, hydrochloride salt (0.10 g, 0.19 mmol), dimethylsulfamoyl chloride (23 ⁇ L, 0.21 mmol) and diisopropylethylamine (73 ⁇ L, 0.42 mmol) in dichloromethane (5 mL) provided N-(I -[(dimethylamino)sulfonyl]piperidin-4-yl ⁇ -7-(phenylsulfonyl)-4-(trifluoromethyl)- lH-indole-3-sulfonamide.
- Example 108 7-(Phenylsulfonyl)-4-(trifluoromethyl)-yV- ⁇ l- [(trifluoromethyI)sulfonyl]piperidin-4-yl ⁇ -lH-indole-3-sulfonamide
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Abstract
Indole sulfonamide compounds or pharmaceutically acceptable salts thereof, are provided, which are modulators of secreted frizzled related protein-1. The compounds, and compositions containing the compounds, can be used to treat a variety of disorders, including osteoporosis. (I) R1 is alkyl, perfluoroalkyl, halo, cyano, or CO2alkyl; R2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl; R3 is optionally substituted aryl. R4 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl; R5 is hydrogen or alkyl; R6 is optionally substituted aryl or heteroaryl; R7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl; and X is absent or SO2.
Description
INDOLE SULFONAMIDES AS SFRP-I MODULATORS
FIELD OF THE INVENTION
[0001] The present invention relates to novel indole sulfonamides that act, for example, as modulators of secreted frizzled-related protein-1. The present invention also relates to processes for the preparation of indole sulfonamides and to their use in treating various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
BACKGROUND OF THE INVENTION
[0002] Bone remodeling, the process by which the adult human skeleton is continuously renewed, is carried out by osteoclasts and osteoblasts, two specialized cell types that originate from hematopoietic and mesenchymal progenitors of the bone marrow, respectively. A continuous and orderly supply of these cells is believed to be essential for skeletal homeostasis, as increased or decreased production of osteoclasts or osteoblasts and/or changes in the rate of their apoptosis are largely responsible for the imbalance between bone resorption and formation that underlies several systemic or localized bone diseases. For example, enhanced osteoclast activity has been found to play a major role in the pathogenesis of postmenopausal osteoporosis, Paget's disease, lytic bone metastases, multiple myeloma, hyperparathyroidism, rheumatoid arthritis, periodontitis, and hypercalcemia of malignancy.
[0003} Numerous genes and gene families (and the polypeptides encoded by them) that participate in the regulation of bone cell production and apoptosis have been identified. Wnt proteins have been identified as a family of growth factors consisting of more than a dozen structurally related molecules that are involved in the regulation of fundamental biological processes such as apoptosis, adipogenesis, embryogenesis, organogenesis, morphogenesis and tumorigenesis (Nusse and Varmus, Cell 1992, 69:1073-1087). Wnt polypeptides are multipotent factors and have biological activities similar to those of other secretory proteins such as
transforming growth factor (TGF)-β, fibroblast growth factors (FGFs), nerve growth factor (NGF), and bone morphogenetic proteins (BMPs).
[0004] Studies indicate that certain Wnt proteins interact with a family of proteins named "frizzled" that act as receptors for Wnt proteins or as components of a Wnt receptor complex (in Moon et al, Cell 1997, 88:725-728; Barth et al, Cnrr. Opin. CellBiυl. 1997, 9:683- 690). Frizzled proteins contain an amino terminal signal sequence for secretion, a cysteine-rich domain (CRD) that is thought to bind Wnt, seven putative transmembrane domains that resemble a G-protein coupled receptor, and a cytoplasmic carboxyl terminus. The Frizzled receptors form a signaling complex with another family of membrane receptors known as the low-density lipoprotein (LDL) receptor-related proteins (LRP) (in Logan & Nusse, Annual Review of Cell & Developmental Biology 2004, 20:781-810; Moon etal, Nature Reviews Genetics 2004, 5:691- 701).
[0005| The first secreted frizzled-related protein (SFRP) was named "Frzb" (for "frizzled motif in bone development") and was purified and cloned from bovine articular cartilage extracts based on its ability to stimulate in vivo chondrogenic activity in rats (Hoang et al, J. Biol. Chem. 1996, 271 :26131-26137; Jones & Jomary, Bioessays 2002, 24:81 1-820). The human homologue of the bovine gene has also been cloned. Unlike the frizzled proteins, however, Frzb does not contain a serpentine transmembrane domain, and appears to be a secreted receptor for Wnt. The Frzb cDNA encodes a 325 amino acid/36,000 dalton protein and is predominantly expressed in the appendicular skeleton. The highest level of expression is in developing long bones and corresponds to epiphyseal chondroblasts; expression declines and disappears toward the ossification center.
[0006] Studies indicate that SFRPs participate in apoptosis. Some SFRPs have thus been identified as "SARPs" for secreted apoptosis related proteins. Additional members of the SFRP family have been identified, and have been shown to be antagonists of Wnt action. There are currently at least five known human SFRP/SARP genes: SFRP-l/FrzA/FRP-l/SARP-2, SFRP-2/SDF-5/SARP-1, SFRP-3/Frzb-l/FrzB/Fritz, SFRP-4 and SFRP-5/SARP-3 (Leimeister et al, Mechanisms of Development 1998, 75:29-42). Secreted frizzled related protein-1 (SFRP- 1) is a Wnt antagonist and is expressed in osteoblasts and osteocytes as well as fibroblasts. Although the precise role that SARPs/SFRPs play in apoptosis is not yet clear, these proteins appear to either suppress or enhance the programmed cell death process. Deletion of SFRP-I in mice has been shown to lead to decreased osteoblast/osteocyte apoptosis and to increased bone
formation. (Bodine, P.V.N, et ai, MoL Endocrinol., 2004, 18(5) 1222-1237.) Deletion of SFRP-I in mice has also been shown to lead to an acceleration of chondrocyte differentiation. (Gaur, T., et al., J. Cell. Physiol., 2006, 208(1) 87-96.) Modulation of SFRP-I with an anti- SFRP-I antibody has been shown to enhance new connective tissue formation resulting in increases in palatal wound healing (Li, C. H. and Amar, S. J. Dent. Research, 2006, 85(4), 374- 378. Overexpression of SFRP-I has also been implicated in autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof by stimulating a pathogenic process of adipogensis (Kumar, S., et. al., J. Clin. Endocrinol. Metab., 2005, 90, 4730-4735).
[0007] A need exists in the art for the identification of modulators of SFRP- 1 that can be used as novel agents for the treatment of bone disorders or bone fractures, including bone resorption disorders such as osteoporosis, and for regulation of bone formation in humans or for other diseases and disorders, such as arthritis, chronic obstructive pulmonary disease, cartilage defects, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
SUMMARY OF THE INVENTION
[0008] The present invention relates to certain indole sulfonamides and to their use, for example, in medical treatment. In one aspect, the invention relates to indole sulfonamides that act as modulators of secreted frizzled related protein- 1. The compounds can be used, for example, to treat various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
[0009] In one aspect, the present invention is directed to compounds of Formula (I):
or pharmaceutically acceptable salts thereof,
wherein:
R1 is alkyl, perfluoroalkyl, halo, cyano, or COialkyl;
R2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl; and
R3 is optionally substituted aryl.
[0010] In another aspect, the present invention is directed to compounds of Formula (H).
or a pharmaceutically acceptable salt thereof, wherein:
R4 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl;
R5 is hydrogen or alkyl;
R6 is optionally substituted aryl or heteroaryl;
R7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl, and
X is absent or SO2.
[001 IJ In other embodiments, the invention relates to compositions comprising at least one compound of Formula I or II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers.
[0012] The present invention also provides methods for treating patients suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof, that comprise administering to the patients a therapeutically effective amount of at least one compound of Formula I or II.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0013] The term "alkyl," as used herein, refers to an optionally substituted saturated aliphatic hydrocarbon chain having 1 to 12 carbon atoms (CM2 alkyl), preferably 1 to 8 carbon atoms (Ci-8 alkyl), more preferably 1 to 6 carbon atoms (Ci-6 alkyl), and even more preferably 1 to 3 carbon atoms (C1.3 alkyl). The term "alkyl" includes straight and branched chains. In one embodiment straight chain alkyl groups have 1 to 8 carbon atoms and branched chain alkyl groups have 3 to 12 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl groups.
[0014] The term "perfluoroalkyl," as used herein, refers to an optionally substituted straight or branched saturated aliphatic hydrocarbon chain of 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, in which all hydrogens are replaced with fluorine.
[0015] The term "alkylcarbonyl," as used herein, refers to the group -C(O)R' where R' is an alkyl group as previously defined.
[0016] The term "alkylaminothiocarbonyl," as used herein, refers to the group - C(S)NHR' where R' is an alkyl group as previously defined.
[0017] The term "carboxyalkylcarbonyl," as used herein, refers to the group -C(O)RX(O)OH where R' is an alkyl group as previously defined.
[0018] The term "cycloalkyl," as used herein, refers to an optionally substituted hydrocarbon ring containing 3 to 12 carbon atoms (C3-12 cycloalkyl), preferably 3 to 6 carbon atoms (C3.6 cycloalkyl). Cycloalkyl groups may be monocyclic, bicyclic, or bridged, and may be saturated or partially unsaturated. "Bridged" cycloalkyl groups contain at least one carbon- carbon bond between two non-adjacent carbon atoms of the cycloalkyl ring.
[0019| The term "heterocycloalkyl," as used herein, refers to a 3 to 12 membered, and more preferably a 5 to 7 membered, optionally substituted heterocyclic ring system comprising one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur, including sulfoxide and sulfonyl. The heterocycloalkyl group may be saturated or partially unsaturated, and may be monocyclic, bicyclic or bridged. Bicyclic heterocycloalkyl groups include a monocytic heterocycloalkyl ring fused to a monocyclic heterocycloalkyl ring, a cycloalkyl ring, an aryl ring, or a heteroaryl ring. "Bridged" heterocycloalkyl groups contain at least one carbon- carbon bond between non-adjacent carbon atoms of the heterocycloalkyl ring.
[0020J The term "spiroheterocycloalkyl," as used herein, refers to two optionally substituted heterocycloalkyl groups, or one optionally substituted cycloalkyl group and one optionally substituted heterocycloalkyl group, as previously defined, that are joined by a single sp3 carbon atom that is the only common member of the two joined rings.
[0021] The term "alkoxy," as used herein, refers to the group -O-R' where R' is an alkyl group as previously defined. Preferably, the alkoxy groups have 1 to 6 carbon atoms (Cj.6 alkoxy).
[0022] The term "alkoxycarbonyl," as used herein, refers to the group -C(O)OR' where R' is an alkyl group as previously defined.
[0023] The term "alkoxycarbonylamino," as used herein, refers to the group -N(H)- C(O)-OR' where R' is an alkyl group as previously defined.
[0024] The term "alkoxycarbonylcarbonyl," as used herein, refers to the group - C(O)C(O)OR' where R' is an alkyl group as previously defined.
[0025] The term "alkoxycarbonylalkylaminothiocarbonyl," as used herein, refers to the group -C(S)-NH-R' -C(O)-OR' where R' is an alkyl group as previously defined.
[0026] The term "hydroxycarbonylcarbonyl," as used herein, refers to the group - C(O)C(O)OH.
[0027] The term "aryl," as used herein refers to an optionally substituted carbocyclic aromatic ring e.g. having 6 to 14 ring carbon atoms (Cδ-π aryl), preferably 6 to 10 ring carbon atoms (Ce-io aryO- Aryl groups may be monocyclic or bicyclic. Exemplary aryl groups include phenyl and naphthyl.
[0028] The term "arylalkyl," as used herein, refers to the group -R'-aryl where aryl is an aryl group as previously defined, and R' is an alkyl group as previously defined.
[0029] The term "arylcarbonyl," as used herein, refers to the group -C(O)-aryl, where aryl is an aryl group as previously defined.
[0030] The term "alkoxycarbonylarylcarbonyl," as used herein, refers to the group - C(O)-aryl-C(O)-OR' where aryl is an aryl group as previously defined and R' is an alkyl group as previously defined.
[0031] The term "carboxyarylaminothiocarbonyl," as used herein, refers to the group - C(S)-NH-aryl-C(O)OH where aryl is an aryl group as previously defined.
[0032] The term "arylaminothiocarbonyl," as used herein, refers to the group -C(S)NH(aryl), where aryl is an aryl group as previously defined.
[0033] The term "arylsulfonyl," as used herein, refers to the group -S(O)2-aryl where aryl is an aryl group as previously defined.
[0034] The term "cyanoarylcarbonyl," as used herein, refers to the group -C(O)-aryl-CN where aryl is an aryl group as previously defined.
[0035J The term "alkylarylcarbonyl," as used herein, refers to the group -C(O)-aryl-R' where R' is an alkyl group as previously defined and aryl is an aryl group as previously defined.
[0036] The term "carboxyarylcarbonyl," as used herein, refers to the group -C(O)-aryl- C(O)OH where aryl is an aryl group as previously defined.
[0037] The term "carboxyarylsulfonyl," as used herein, refers to the group -Sθ2-aryl- C(O)OH where aryl is an aryl group as previously defined.
[0038] The term "heteroaryl," as used herein refers to an optionally substituted 5 to 10 membered monocyclic or bicyclic carbon containing aromatic ring having 1 to 3 of its ring members independently selected from nitrogen, sulfur and oxygen. In one embodiment monocyclic rings preferably have 5 to 6 ring members, and bicyclic rings preferably have 8 to 10 ring members. Examples of heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, and quinazolinyl.
[0039] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine or iodine.
[0040] The term "nitro" as used herein, refers to -NO2.
[0041] The term "sulfonyl" refers to -SO2-.
10042] The term "sulfoxide" refers to -SO-.
[0043| As used herein, the terms "optionally substituted" or "substituted or unsubstituted" are intended to refer to the optional replacement of up to four hydrogen atoms with up to four independently selected substituent groups as defined herein. Unless otherwise specificed, suitable substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, alkyl, perfluoroallcyl, alkyamino, diaikylamino, alkoxy, alkylcarbonyl, arylcarbonyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, haloalkyl, perfluoroalkylalkyl, alkenyl, alkynyl, arylalkyl and the like. Substituent groups that have one or more available hydrogen atoms can in
turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions. For example, the term "optionally substituted aryl" is intended to mean an aryl group that can optionaly have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the aryl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).
[0044] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkoxycabonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.
[0045] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan
[0046] The term "protecting group" with respect to amine groups, hydroxyl groups and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art, such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxy methyl ether, 2- methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate. Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB, benzyl, and dithiosuccinimide; and others. Examples of protected or capped sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl
thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
[0047J Reference to "activated" or "an activating group" or "RA" as used herein indicates having an electrophilic moiety bound to a substituent, capable of being displaced by a nucleophile. Examples of preferred activating groups are halogens, such as Cl3 Br or I, and F; triflate; mesylate, or tosylate; esters; aldehydes; ketones; epoxides; and the like. An example of an activated group is acetylchloride, which is readily attacked by a nucleophile, such as piperidine group to form a N-acetylpiperidine functionality.
[0048] The term "deprotecting" refers to removal of a protecting group, such as removal of a benzyl or BOC group bound to an amine. Deprotecting may be preformed by heating and/or addition of reagents capable of removing protecting groups. One preferred method of removing BOC groups from amino groups is to add HCl in ethyl acetate. Many deprotecting reactions are well known in the art and are described in Protective Groups in Organic Synthesis, Greene, T. W., John Wiley & Sons, New York, NY, (1st Edition, 1981).
[0049] The term "therapeutically effective amount," as used herein, refers to the amount of a compound of Formula 1 or II that, when administered to a patient, is effective to at least partially treat a condition from which the patient is suffering or is suspected to suffer. Such conditions include, but are not limited to, osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, and leiomyoma.
[0050] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" includes acid addition salts, namely salts derived from treating a compound of formula I or II with an organic or inorganic acids or bases. Where the compound having formula I or II has an acidic function, the term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" includes salts derived from bases, for instance, sodium salts.
[0051] The term "patient," as used herein, refers to a mammal.
[0052] The terms "administer," "administering," or "administration," as used herein, refer to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.
[0053] The terms "treat" and "treating," as used herein, refer to partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
[0054] The terms "suffer" and "suffering," as used herein, refer to one or more conditions with which a patient has been diagnosed, or is suspected to have.
[0055] Certain embodiments of the invention relate to compounds of Formula (I)'
or pharmaceutically acceptable salts thereof, wherein:
R1 is alkyl, perfluoroalkyl, halo, cyano, or CCtølkyl;
R2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl; and
R3 is optionally substituted aryl.
[0056] In certain embodiments of the invention, the aryl, alkyl, cycloalkyl, heterocycloalkyl, and spiroheterocycloalkyl groups found in compounds of Formula I are optionally substituted with one or more substituents that include, for example, hydrogen, branched and unbranched alkyl, perfluoroalkyl, bromo, chloro, fiuoro, iodo, cyano, CO2alkyl, CO2H, phenyl, hydroxy, alkoxy, perfluoroalkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, and diarylamino. In another embodiment the aryl, alkyl, cycloalkyl, heterocycloalkyl, and spiroheterocycloalkyl groups found in compounds of Formula I are optionally substituted with 1-3 substituents selected from hydrogen, Ci-C6 alkyl, Ci-C6 perfluoroalkyl, halo, cyano, CO2-(Ci-Ce) alkyl, CO2H, phenyl, hydroxy, Ci-Cβ alkoxy, Ci-Ce perfluoroalkoxy, C6-C10 aryloxy, amino, Ci-Cβ alkylamino, di(Ci-C6)alkylamino, C6-C10 arylamino, and di(C6-Cio)arylamino.
[0057] In certain embodiments of the invention, R1 of Formula I is C1-C3 alkyl, C1-C3 perfluoroalkyl, halo, cyano, or CO2C1-C3 alkyl. In preferred embodiments, R1 is methyl, ethyl,
isopropyl, trifluoromethyl, bromo, chloro, cyano, or Cθ2methyl. In particularly preferred embodiments, R1 is trifluoromethyl, isopropyl, or bromo.
[0058| Other aspects of the invention are directed to compounds of Formula I in which R2 is C1-C3 alkyl, substituted C1-Cs alkyl, cyclohexyl, substituted cyclohexyl, piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, substituted tetrahydrothiopyranyl, or 1,4- di oxaspi rodecany 1. f0059| In certain embodiments of the invention, the substituents for the piperidinyl groups of R2 of Formula I are selected from alkyl, alkoxycarbonyl, substituted alkylcarbonyl, substituted arylcarbonyl, substituted arylsulfonyl, alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, substituted arylaminothiocarbonyl, and substituted alkylaminothiocarbonyl. In preferred embodiments, the piperidinyl group substituents are selected from alkyl, alkoxycarbonyl, carboxyalkylcarbonyl, cyanoarylcarbonyl, alkylarylcarbonyl, carboxyarylcarbonyl, alkoxycarbonylarylcarbonyl, carboxyarylsulfonyl, alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, carboxyarylaminothiocarbonyl, and alkoxycarbonylalkylaminothiocarbonyl. In particularly preferred embodiments, the piperidinyl group substituents are selected from methyl, ethoxycarbonyl, tertbutyloxycarbonyl, carboxypropylcarbonyl, methoxycarbonylphenylcarbonyl, carboxyphenylcarbonyl, cyanophenylcarbonyl, tertbutylphenylcarbonyl, carboxyphenylsulfonyl, methoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, carboxyphenylaminothiocarbonyl, and methoxycarbonylmethyleneaminothiocarbonyl.
[0060] In other embodiments of the invention, the substituents for the alky groups of R2 of Formula I are selected from alkoxy, heterocycloalkyl, aryl, substituted aryl, heteroaryl, cyano, hydroxyl, and hydroxy sulfonyl. In preferred embodiments, the alkyl group substituents are selected from methoxy, morpholinyl, piperidinyl, thiomorpholinyl, tetrahydropyranyl, phenyl, carboxyphenyl, pyridyl, imidazolyl, benzoimidazolyl, cyano, hydroxyl, and hydroxy sulfonyl.
[00611 In further aspects of the invention, the substituents for the cyclohexyl groups of R2 of Formula I are selected from hydroxyl, oxo, and alkyloxycarbonylamino. In preferred aspects, the cyclohexyl group substituents are selected from hydroxyl, oxo, and tertbutyloxycarbonylamino.
[0062] In additional embodiments of the invention, the substituents for the tetrahydrofuranyl and tetrahydrothiopyranyl groups of R2 of Formula I are oxo groups.
[0063] In still further aspects of the invention, the substituents for the pyrrolidinyl groups of R2 of Formula I are arylalkyl groups, preferably phenylmethyl groups.
[0064J Other aspects of the invention are directed to compounds of Formula I in which R3 is phenyl or substituted phenyl. In preferred embodiments of the invention, R3 is phenyl.
[0065] Additional embodiments of the invention relate to compounds of Formula I in which R1 is methyl, ethyl, isopropyl, trifluoromethyl, bromo, chloro, cyano, or Cθ2methyl; R2 is C1-C3 alkyl, substituted C1-C3 alkyl, cyclohexyl, substituted cyclohexyl, piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, substituted tetrahydrothiopyranyl, or 1,4- dioxaspirodecanyl; and R3 is phenyl or substituted phenyl.
[0066] Specific, representative compounds of Formula I include: l-CphenylsulfonyO-N-piperidin^-yl-ΦCtrifluoromethy^-lH-indole-S-sulfonamide;
3-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidin- l-yl]sulfonyl}benzoic acid; methyl 4-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lΗ-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoate;
4-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoic acid; methyl N-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonothioyl}glycinate;
N-(2-oxotetrahydrofuran-3-yl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole- 3- sulfonamide;
5-oxo-5-[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]pentanoic acid;
4-[2-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)ethyl]benzoic acid;
N-^ans^-aminocyclohexyO-l^phenylsulfony^^-OrifluoromethyO-lH-indole-S- sulfonamide; l-CphenylsulfonyO-N-^etrahydro-ZH-thiopyran^-yl^-OrifluoromethyO-lH- indole-3- sulfonamide;
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsuIfonyl)-4- (trifluoromethyl)- lH-indole-3-sulfonamide;
N-(l-oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenyIsulfonyl)-4-(trifluoromethyl)- IH- indole-3-sulfonamide;
N-^ans-ΦhydroxycyclohexyO-l^phenylsulfonyO^-ttrifluoromethyO-lH-indole- S- sulfonamide;
^(^oxocyclohexyO-l-Cphenylsulfonyl^-^rifluoromethy^-lH-indole-S- sulfonamide;
N-l,4-dioxaspiro[4.5]dec-8-yl-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole- 3- sulfonamide; l-CphenylsulfonyO-N^-pyridin-S-ylethylJ^^trifluororaethyO-lH-indole-S- sulfonamide; methyl oxo[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetate; oxo[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetic acid; l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide; l-(phenylsulfonyl)-iV-(2-pyridin-4-ylethyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide; l-(phenylsulfonyl)-iV-(pyridin-3-ylmethyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide, l-(phenylsulfonyl)-N-pyrrolidin-3-yl-4-(trifluoromethyl)-lH-indole-3-sulfonamide; l-(phenylsulfonyl)-N-(pyridin-4-ylmethyl)-4-(trifluoromethyI)-lH-indole-3-sulfonamide; l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide; l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide;
^/•/-butyM-dll-CphenylsulfonyO^-CtrifluoromethyO-lH-indol-S- yl]sulfonyl}amino)piperidine-l-carboxylate;
N-[(3Λ)-l-benzylpyrrolidin-3-yI]-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide; tert-butyl [trans-4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lΗ-indol-3- yl]sulfonyl}amino)cyclohexyl]carbamate;
4-{[3-[(piperidin-4-ylamino)sulfonyl]-4-(trifluoromethyl)-lH-indol-l- yl]sulfonyl}benzoic acid;
3-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indoI-3-yl]sulfonyl}amino)propane-l- sulfonic acid;
l-(phenylsulfonyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-4-(trifluoromethyl)-lH-indole- 3-sulfonamide;
N-cyclohexyl-l-tphenylsulfonyO^^trifluoromethyl^lH-indole-S-sulfonamide;
N-P^lH-benzimidazol^-yOethyll-l-CphenylsulfonylΗ-^riiluoromethyO-lH-indole-S- sulfonamide;
5-[4-({[4-isopropyl-l-(phenylsuIfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l-yl]-5- oxopentanoic acid;
N-(frα«5-4-hydroxycyclohexyl)-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3- sulfon amide; tert-buty\ 4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine- 1-carboxylate;
4-isopropyl-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide;
3-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-iηdol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid;
4-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid;
4-isopropyl-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-i sopropyl- 1 -(phenyl sulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)- lH-indole-3 - sulfonamide;
N-Cljl-dioxidotetrahydro-^-thiopyran^-y^^-isopropyl-l^phenylsulfonyO-lH-indole- 3-sulfonamide;
4-i sopropyl -N-( 1 -oxidotetrahy dro-2H-thi opy ran-4-y I)- 1 -(phenyl sul fonyl )- lH-i ndol e-3 - sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
N-[3-(lH-imidazol-l-yl)propyl]-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3- sulfonamide;
4-isopropyl-N-(2-moφholin-4-ylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-isopropyl-N-(2-phenylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide; ethyl 4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-isopropyl-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-isopropyl- 1 -(phenyl sulfonyl)-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]- 1 H-indole-3- sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide;
N-benzyl-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-isopropyl-Λ/-(3-phenylpropyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
3-({[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]carbonothioyl}amino)benzoic acid;
N-(2-hydroxy-2-pyridin-3-ylethyl)-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3- sulfonamide;
4-isopropyl-l -(phenyl sulfonyl)-N-(2-thiomoφholin-4-yIethyl)-lH-indole-3-sulfonamide;
4-isopropyl-Ν-(l-methylpiperidin-4-yl)-l-(phenylsulfonyl)-lΗ-indole-3-sulfonamide; methyl 4-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin- 1 -yl]carbonyl }benzoate;
4-bromo-l-(phenylsulfoπyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide; tert-butyl 4-({[4-bromo-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-bromo-l-(phenylsulfonyl)-N-piperidin-4-yl-l//-indole-3-sulfonamide;
4-bromo-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide;
4-bromo-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-bromo-l-(phenylsulfonyl)-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-lH-indole-3- sulfonamide;
4-bromo-N-(2-phenylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-bromo-N-[l-(4-cyanobenzoyl)piperidin-4-yl]-l-(phenylsulfonyl)-lH-indole-3- sulfonamide;
4-ethyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide;
4-ethyl-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide; tert-buty\ 4-({[4-ethyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-ethyl-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide;
4-ethyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide;
4-ethyl-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide; ethyl 4-({[4-chloro-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-chloro-N-(cyanomethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
Ν-fl^-tert-butylbenzoyOpiperidin^-ylj^-cyano-l-CphenylsulfonyO-lΗ-indole-S- sulfonamide;
4-cyano-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide;
/er/-butyl 4-({[4-cyano-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-cyano-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide,
4-cyano-l-(ρhenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-cyano-N-(2-methoxyethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-cyano-N-(2-morpholin-4-ylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-cyano-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
4-cyano-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-cyano-l-(phenylsulfonyl)-N-(2-piperidin-l-ylethyl)-lH-indole-3-sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(2-piperidin-l-ylethyl)-lH-indole-3-sulfonamide;
4-[2-({[4-(methoxycaitonyl)-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)ethyl]benzoic acid;
methyl l-(phenylsulfonyl)-3-{[(2-pyridin-3-ylethyl)amino]sulfonyl}-lH-indole-4- carboxylate; methyl l-(phenylsulfonyI)-3-{[(2-pyridin-4-ylethyl)amino]sulfonyl}-lH-indole-4- carboxylate; methyl 3-{[(/rø/7s-4-hydroxycyclohexyl)amino]sulfonyl}-l-(phenylsulfonyl)-lH-indole- 4-carboxylate; and
4-isopropyl-l-(phenylsulfonyl>N-(2,2,6,6-tetramethylpiperidin-4-yl)-lH-indole-3- sulfonamide.
[0067] Preferred compounds of Formula I include: l-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH-indole-3-sulfonamide;
3-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidin- l-yl]sulfonyl}benzoic acid;
4-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyi)-lΗ-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoic acid; methyl N-{[4-({[l -(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonothioyl}glycinate;
N-(2-oxotetrahydrofuran-3-yl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole- 3- sulfonamide;
5-oxo-5-[4-({[l-(phenylsulfonyl)-4-(trifluorornethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]pentanoic acid;
4-[2-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl }amino)ethyl]benzoic acid;
N-(trans-4-aminocyclohexyl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide;
5-[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l-yl]-5- oxopentanoic acid;
N-(/rα/75-4-hydroxycyclohexyl)-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3- sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide; and
3-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid.
II
or pharmaceutically acceptable salts thereof, wherein:
R4 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl;
R5 is hydrogen or alkyl;
R6 is optionally substituted aryl or heteroaryl;
R7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl; and
X is absent or SO2.
[0069] In certain embodiments of the invention, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups present in compounds of Formula II are optionally substituted with one or more substituents that include, for example, halogen, CN, OH, NO2, amino, -alkylamino, -dialkylamino, alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, C1 to Cs alkoxy, Ci to C3 perfluoroalkyl, Ci to C3 perfluoroalkoxy, -0-(CH2)o-3-aryl, -S-(CH2)o-3-aryl, alkyl carbonyl, including -CO-(Ci to C6 alkyl) and -CO-(Ci to C6 substituted alkyl), -CO-(CH2)o-3-aryl, -SO2-(Ci to C6 alkyl), -SO2-(Ci to C6 substituted alkyl), -SO2-(CH2)0.3-aryl, -COOH, alkylcarboxy, including -COO-(Ci to C6 alkyl) and -COO-(Ci to C6 substituted alkyl), -COO-(CH2)o-3-aryl, and -CON(R5)Z.
[0070J In particular embodiments of the invention, X of Formula II is SO2. In other embodiments, X is absent.
(0071] Other aspects of the invention are directed to compounds of Foπnula II in which R4 is optionally substituted cycloalkyl, or heterocycloalkyl. In preferred embodiments, R4 is optionally substituted heterocycloalkyl, and in particularly preferred embodiments, R4 is optionally substituted piperidinyl.
[0072] In certain embodiments of the invention, the optional substituents for the alkyl, cycloalkyl, and heterocycloalkyl groups of R4 of Formula II are selected from alkyl, aryl, alkoxy,
alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl , dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylsulfonyl and perfluoroalkylcarbonyl wherein any arylcarbonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl,or hetercycloalkylcarbonyl portion of R4 may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, oxo, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl.
[0073] The optional substituents for the alkyl, cycloalkyl, and heterocycloalkyl groups of R1 are preferably tertbutyloxy, trifluoromethylcarbonyl, tertbutyloxycarbonyl, trifluoromethylsulfonyl, dimethylaminosulfonyl, or carboxyphenylsulfonyl.
[0074] Other aspects of the invention relate to compounds of Formula IT in which R5 is hydrogen, methyl, ethyl, propyl, or isopropyl. R5 is preferably hydrogen or methyl.
[0075] Still further embodiments of the invention relate to compounds of Formula π in which R6 is aryl and X is either sulfonyl or is absent. In preferred embodiments, R6 is phenyl and X is either sulfonyl or is absent.
[0076] Additional aspects of the invention relate to compounds of Formula II in which R7 is C1-C3 alkyl, C1-C3 perfluoroalkyl, halo, cyano, or CO2C1-C3 alkyl. In preferred embodiments, R7 is methyl, ethyl, isopropyl, trifiuoromethyl, bromo, chloro, cyano, Or COaCH3. And in particularly preferred embodiments, R7 is trifiuoromethyl.
[0077] Certain embodiments of the invention are directed to compounds of Formula II in which R1 is optionally substituted heterocycloalkyl; R2 is hydrogen, methyl, ethyl, or propyl; R3 is phenyl; and R4 is methyl, ethyl, isopropyl, trifiuoromethyl, bromo, chloro, cyano, or CO2CH3.
[0078] Specific, representative compounds of Formula II include:
/<?r*-Butyl 4-({[7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate;
7-(Phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH-indole-3-sulfonaraide;
T^PhenylsulfonyO-N-fl-^rifluoroacetyOpipeπdin^-ylJ-^CtrifluoromethyO-lH-indole-S- sulfonamide;
N-[\ -(2,2-Dimethylpropanoyl)piperidin-4-yl]-7-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indole-3-sulfonamide; jV-{ l-[(Dimethylamino)sulfonyl]piperidin-4-yl}-7-(phenylsulfonyl)-4-(trifluoromethyl)- lH-indole-3-sulfonamide;
3-{[4-({[7-(Phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidin- l-yl]sulfonyl}benzoic acid;
7-(Phenylsulfonyl)-4-(trifluoromethyl)-N-{l-[(trifluoromethyl)sulfonyl]piperidin-4-yl}- lH-indole-3-sulfonamide; terl-Butyl 4-({[l-methyl-7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate; and l-Methyl-7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH-indole-3- sulfonamide.
[0079] Compounds of Formula 1 and Il may be used to modulate the activity of secreted frizzled related protein-1. Such compounds are of interest for the treatment of osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
[0080J In certain embodiments, the present invention therefore provides methods of treating, preventing, inhibiting, or alleviating each of the maladies listed above in a mammal, preferably in a human, comprising administering a therapeutically effective amount of a compound of Formula I or II or a pharmaceutically acceptable salt thereof to a patient suspected to suffer from such a malady.
[0081] In other embodiments, the invention relates to compositions comprising at least one compound of Formula I or II, or a steroisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the bone. In certain embodiments, the compositions comprise mixtures of one or more compounds of Formula I or II.
[0082] Certain of the compounds of Formula I and II contain stereogenic carbon atoms or other chiral elements and thus give rise to stereoisomers, including enantiomers and diastereomers. The invention generally relates to all stereoisomers of the compounds of Formula I or IT, as well as to mixtures of the stereoisomers. Throughout this application, the name of a compound without indication as to the absolute configuration of an asymmetric center is intended to embrace the individual stereoisomers as well as mixtures of stereoisomers. Reference to optical rotation [(+), (-) and (±)] is utilized to distinguish the enantiomers from one another and from the racemate. Furthermore, throughout this application, the designations R* and S* are used to indicate relative stereochemistry, employing the Chemical Abstracts convention which automatically assigns R* to the lowest numbered asymmetric center.
[0083] An enantiomer can, in some embodiments of the invention, be provided substantially free of the corresponding enantiomer. Thus, reference to an enantiomer as being substantially free of the corresponding enantiomer indicates that it is isolated or separated via separation techniques or prepared so as to be substantially free of the corresponding enantiomer. "Substantially free," as used herein, means that a significantly lesser proportion of the corresponding enantiomer is present. In preferred embodiments, less than about 90 % by weight of the corresponding enantiomer is present relative to desired enantiomer, more preferably less than about 1% by weight. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or preferred enantiomers, can be prepared by methods described herein. Methods for the preparation of enantiomers are described, for example, in Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et ai, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972), each of which is hereby incorporated by reference in its entirety. Process of Preparation of Compounds of Formula 1:
[0084] Another aspect of the invention provides a process for the preparation of a compound of formula (I):
I wherein:
R1 is alkyl, perfluoroalkyl, halo, cyano, or CO∑alkyl;
R2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl; and
R3 is optionally substituted aryl; the process comprising: contacting H2N-R2 with a compound of formula IA:
IA.
[0085J In a more particular embodiment thereof, the compound of formula IA is prepared by: contacting chlorosulfonic acid with a compound of formula IB:
[0086] In a more particular embodiment thereof, the process further comprises reacting the chlorosulfonic acid contacted compound of formula IB with PCI5.
[0087| In a more particular embodiment thereof, the compound of formula IB is prepared by: contacting R3-SCh-Cl with a compound of formula IC:
IC.
[0088] In a more particular embodiment thereof, the compound of formula IC is synthesized by:
(a) contacting a N,N-dimethylformamide dimethyl acetal with a compound of formula ED:
[0089] In a more particular embodiment thereof, the reducing metal is iron and the acid is acetic acid.
Process of Preparation of Compounds of Formula JI:
[0090] Another aspect of the invention provides a process for the preparation of a compound of formula IIA:
ΠA wherein:
R4 is optionally substituted alkyl, cycloalkyl, or heterocycioalkyl; R6 is optionally substituted aryl or heteroaryl; R7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl; and X is absent or SO2;
the process comprising: contacting a H2N-R4 with a compound of formula HB:
IIB.
[0091] Another embodiment comprises contacting the compound of formula HA with a compound of formula: RA-R5, to form a compound of formula II:
RA is an activating group; and
R5 is alkyl or substituted alkyl. a more particular embodiment thereof, RA is Cl, Br, I, tosylate, mesylate, triflate, an ester, an epoxide or an aldehyde.
[0092J In a more particular embodiment thereof, the compound of formula HA is prepared by: contacting sulfonyl chloride with a compound of formula 1IC:
lie.
[0093] In a more particular embodiment thereof, the process further comprises reacting the sulfonyl chloride contacted compound of formula UC with PCI5.
[0094] In a more particular embodiment thereof, the compound of formula IIC is prepared by: contacting vinylmagnesium bromide with a compound of formula TID:
IID.
[0095] In a more particular embodiment thereof, the compound of formula IID is prepared by: contacting RB-X-R6 with a compound of formula HE:
wherein, hal is halogen; and if X is SO2 then RB is hydrogen or if X is absent then RB is a boronic acid.
[0096] The following synthetic schemes are designed to illustrate, but not limit, general procedures for the preparation of compounds of Formula I and II. The reagents used can be either commercially obtained or can be prepared by standard procedures described in the literature.
Synthesis of Compounds of Formula I:
[0097J As shown in Scheme 1, a 4-substituted indole 1 is treated sequentially with an appropriate base, such as sodium hydride, in an appropriate solvent, such as DMF or THF, and then a sulfonyl chloride, such as benzenesulfonyl chloride, to produce the corresponding N- sulfonyl indole 2. The N-sulfonyl indole 2 can then be sulfonylated with an appropriate sulfonating agent, such as chlorosulfonic acid or sulfuric acid, in the presence or absence of a suitable solvent, such as dichloromethane or chloroform, to produce either the indole 3-sulfonyl chloride 3 directly or the indole 3-sulfonic acid which can be converted to the indole 3-sulfonyl chloride 3 by treatment with an appropriate chlorinating agent, such as phosphorous pentachloride in phosphorous oxychloride. The indole 3-sulfonyl chloride 3 can then be condensed with various primary or secondary amines in the presence of a base, such as pyridine or triethylamine, in a suitable solvent, such as dichloromethane or DMF, to provide the target compound 4. If a secondary amine is utilized in the preparation of 4, the nitrogen-protecting group can be cleaved by standard deprotection chemistry, such as cleavage of the 2,4- dimethoxybenzyl group under acidic conditions. Additionally, if an amine containing a carbonyl protecting group, such as an acetal or ketal, is utilized, this protecting group can be removed by standard deprotection chemistry. Additionally, if an amine containing an ester group is utilized, the ester group could be hydrolyzed to its corresponding acid or reduced to its corresponding alcohol by standard techniques.
[0098] For examples incorporating a substituted 4-aminopiperidine group at R2, the targets are prepared from 4a or 4b as shown in Scheme 2. Treatment of 4a or 4b with a suitable acid, such as trifluoroacetic acid, affords the deprotected piperidine 4c. Treatment of 4c with an appropriate electrophile, such as an acid chloride, acid anhydride, sulfonyl chloride, isocyanate, or isothiocyanate in the presence of a base, such as triethylamine or pyridine, provides the target
compounds. Compound 4c can also be treated with a carboxylic acid in the presence of activating agents, such as dicyclohexylcarbodiimide and dimethylaminopyridine, with a base, such as triethylamine or pyridine, to provide the corresponding amides.
[0099] Additionally, compound 4a can be used to prepare a variety of substitutions at the R3 position as shown in Scheme 3. Treatment of the indole sulfonamide 4a with a suitable base, such as potassium hydroxide, in a suitable solvent, such as methanol, provides the indole 4e. Indole 4e can be treated sequentially with an appropriate base, such as sodium hydride, in an appropriate solvent, such as DMF or THF, and then a sulfonyl chloride, such as a substituted benzenesulfonyl chloride, to produce the corresponding N-sulfonyl indole 4a. This differentially substituted indole can be further manipulated as described in Scheme 2.
[0100] Additionally, when the amine in Scheme 1 is tetrahydro-thiopyran-4-ylamine, the resulting target compound 4f can be treated with an appropriate oxidizing agent, such as oxone or meta-chloroperoxybenzoic acid, to produce the sulfoxide 4g as shown in Scheme 4. The sulfoxide diasteroemers 4g can be separated or they can be further oxidized to the sulfone 4h. Alternatively, the thiopyran 4f can be converted directly to the sulfone 4h by the addition of excess oxidizing agent.
Scheme 4
[0101| If the required 4-substituted indole 1 is not commercially available, it can be prepared by routes known in the literature. One route is depicted in Scheme 5 (Clark, Robin D.; Repke, David B. J. Heterocycl. Chem. 1985, 22, 121-125) and another in Scheme 6 (Muratake, Hideaki; Natsume, Mitsutaka Heterocycles 1990, 31, 683-690).
Scheme 5
Synthesis of compounds of Formula II:
[0102J The following synthetic schemes are designed to illustrate, but not limit, general procedures for the preparation of compounds of Formula II. The reagents used can be either commercially obtained or can be prepared by standard procedures described in the literature.
[0103] As shown in Scheme 7, an appropriately substituted nitrobenzene A, such as 4- chloro-3-nitrobenzotrifluoride or 4-bromo-3-nitrobenzotrifluoride, is treated with an appropriate sulfinic acid salt, such as benzene sulfinic acid sodium salt, in a suitable solvent, such as dimethylsulfoxide, at room temperature or elevated temperatures, such as 60 0C, to yield the substituted nitro benzene B, where X=SO2. Alternatively, an appropriately substituted nitrobenzene A, such as 4-chloro-3-nitrobenzotrifluoride or 4-bromo-3-nitrobenzotrifluoride, can
be coupled with an appropriately substituted aromatic compound, such as an arylboronic acid or aryl stannane, utilizing standard coupling conditions to afford nitro benzene B, where X=a covalent bond. Treatment of the nitrobenzene B with vinylmagnesium bromide at low temperature, such as -40 0C, in a suitable solvent, such as THF, followed by treatment with an aqueous acid, such as saturated ammonium chloride, at this same low temperature provides the indole C upon warming to room temperature. When R5 is not H, indole C can be treated with a base, such as sodium hydride, in an appropriate solvent, such as DMF, and then treated with an electrophile, such as iodomethane, to provide substituted indoles D. Indoles C or D can be treated with a sulfonylating agent, such as chlorosulfonic acid, in a suitable solvent, such as dichloromethane, or in the absence of solvent to produce the sulfonyl chlorides E. The sulfonyl chlorides E can be treated with amines in the presence of a base, such as triethylamine or diisopropylethylamine, in an appropriate solvent, such as dimethylformamide or dichloromethane, to generate the target molecules.
[0104] For examples incorporating a substituted 4-aminopiperidine group at R4, the targets are prepared from F.I as shown in Scheme 8. Treatment of F.I with a suitable acid, such as trifluoroacetic acid, affords the deprotected piperidine G. Treatment of G with an appropriate electrophile, such as an acid chloride, acid anhydride, sulfonyl chloride, isocyanate, or isothiocyanate in the presence of a base, such as triethylamine or pyridine, provides the target compounds H. Compound G can also be treated with a carboxylic acid in the presence of activating agents, such as dicyclohexylcarbodiimide and dimethylaminopyridine, with a base, such as triethylamine or pyridine, to provide the corresponding amides H.
Scheme 8
F.1 H
[0105] In certain embodiments, the invention relates to compositions comprising at least one compound of Formula I or II, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions are prepared in accordance with general pharmaceutical formulation procedures, such as, for example, those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.
[0106J The compounds of Formula I and II can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99 % of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
|0107] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils {e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
[0108] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.
[0109| The compounds of Formula ϊ and II can be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of Formula I and II can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of Formula I and II can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable. A variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
[0110] Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
[0111] The amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of Formula I or II are provided to a patient already suffering from a disease in an amount sufficient
to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective amount." The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age, and response pattern of the patient. The compounds can be administered orally, rectally, parenterally, or topically to the skin and mucosa. The usual daily dose depends on the specific compound, method of treatment and condition treated. The usual daily dose is 0.01 - 1000 mg/kg for oral application, preferably 0.5 - 500 mg/kg, and 0.1 - 100 mg/kg for parenteral application, preferably 0.5 - 50 mg/kg.
[0112] In certain embodiments, the present invention is directed to prodrugs of compounds of Formula I and II. The term "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I and II. Various forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). " Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al, Journal of Drug Delivery Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is hereby incorporated by reference in its entirety.
[0113] The following examples are illustrative of certain embodiments of the invention and should not be considered to limit the scope of the invention. ACD NamePro software was employed to generate IUPAC names for the following examples. The IUPAC names of the following examples are indicative of the neutral or free base forms. Compounds were either isolated as a free base or the corresponding hydrochloride salt as indicated in the experimental procedure.
[01141 Step 1. Dimethyl-[2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl]-amine
[0115] To a solution of 2-methyl-3-nitrobenzotrifIuoride (5.0 g, 24 mmol) in dimethylformamide (30 mL) was added N,N-dimethylformamide dimethyl acetal (18 mL, 130 mmol). The reaction was heated to reflux for 6 hours and then poured onto ice/water and extracted with ethyl acetate. Washed the organic layer with sodium bicarbonate, ammonium chloride, and sodium chloride. Dried the organic layer with magnesium sulfate and concentrated to give dimethyl-[2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl]-amine (6.3 g crude, 100%)
[0116] Step 2. 4-Trifluoromethyl-lH-indole
[0117] To a solution of dimethyl-[2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl]-amine (6.3 g, 24 mmol) in acetic acid (150 mL) was added iron powder (4.3 g, 77 mmol). The reaction was heated to reflux overnight under nitrogen. Upon cooling, the reaction mixture was diluted with 2.0 M HCl and the aqueous phase was extracted with ethyl acetate. The organic layer was neutralized with a saturated solution of potassium carbonate and extracted. Washed
organic layer with sodium bicarbonate followed by sodium chloride. Dried with magnesium sulfate and concentrated to give 4-trifluoromethyl-lH-indole (4.5 g, 100%).
[0118] Step 3. l-Benzenesulfonyl-4-trifluoromethyl-lH-indole
[0119] To a slurry of 60 % sodium hydride (2.4 g, 61 mmol) in dimethylformamide (125 mL) at 00C was added 4-trifluoromethyl-lH-indole (4.5 g, 24 mmol). The reaction was stirred at 00C for thirty minutes and then benzenesulfonyl chloride (3.8 mL, 30 mmol) was added drop wise to the reaction. The reaction was stirred for three hours allowing it to warm to room temperature and then poured onto ice/water and extracted with ethyl acetate. Washed the organic layer with sodium bicarbonate, ammonium chloride, and sodium chloride. Dried the organic layer with magnesium sulfate and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of l-benzenesulfonyl-4-trifluoromethyl-lH-indole (7.0 g, 89 %).
[0120] Step 4. l-BenzenesulfonyM-trifluoromethyl-lH-indole-S-sulfonic acid
[0121 j To a solution of l-benzenesulfonyl-4-trifluoromethyl-lH-indole (3.5 g, 11 mmol) in dichloromethane (60 mL) at 00C was added dropwise chlorosulfonic acid (0.78 mL, 12 mmol) in dichloromethane (10 mL). Stirred at 00C for two hours and a precipitate formed. Filtered the precipitate and washed with dichloromethane to give l-benzenesulfonyl-4- trifluoromethyl-lH-indole-3-sulfonic acid (4.1 g, 93%).
[0122] Step 5. l-Benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl chloride
[0123] To slurry of l-BenzenesulfonyM-trifiuoromethyl-lH-indole^-sulfonic acid (4.1 g, 10 mmol) in phosphorus oxychloride (25 mL) was added phosphorus pentachloride (2.5 g, 12 mmol). Reaction was heated to 1000C for three hours. Reaction was slowly poured onto ice/water and extracted with ethyl acetate. Washed organic layer with ammonium chloride solution. Dried with magnesium sulfate and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl chloride (2.9 g, 67%).
[0124J Step 6. 4-(2,4-Dimethoxy-benzylamino)-piperidine-l-carboxylic acid tert-butyl ester
[0125] To a solution of 2,4-dimethoxybenzylamine (6.0 g, 36 mmol) in dichloromethane (200 mL) was added l-Boc-4-piperidone (7.1 g, 36 mmol). The solution was stirred for 30 minutes and then sodium triacetoxyborohydride (1 1 g, 50 mmol) was added portion wise to the reaction. The reaction was stirred overnight at room temperature under nitrogen. Reaction was washed with saturated bicarbonate followed by ammonium chloride. Dried the organic layer with magnesium sulfate and concentrated to give 4-(2,4-dimethoxy-benzylamino)- piperidine-1-carboxylic acid tert-butyl ester (12.1 g, 96%).
[0126] Step 7. 4-[(l-Benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl)-(2,4- dimethoxy-benzyl)-amino]-piperidine-l-carboxylic acid tert-butyl ester
|0127J To a solution of 1 -benzenesulfonyl-4-trifluoromethyl-l H-indole-3-sulfonyl chloride (3.3 g, 7.8 mmol) and 4-(2,4-dimethoxy-benzylamino)-piperidine-l-carboxylic acid tert- butyl ester (4.1g, 12 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (3.4 mL, 19 mmol). The reaction was stirred overnight at room temperature under nitrogen. Reaction was washed with ammonium chloride follow by sodium bicarbonate. Dried with magnesium sulfate and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 4-[(l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl)-(2,4-dimethoxy- benzyl)-amino]-piperidine-l-carboxylic acid tert-butyl ester (4.0 g, 70%).
[0128] Step 8. l-BenzenesulfonyM-trifluoromethyl-lH-indole-S-sulfonic acid piperidin-4- ylamide hydrochloric acid
[0129| 4-[(l-Benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl)-(2,4- dimethoxy-benzyl)-amino]-piperidine-l-carboxylic acid tert-butyl ester (4.Og, 5.4 mmol) was dissolved in 25% trifluoroacetic acid/dichlorom ethane (50 mL) and the reaction was stirred under nitrogen overnight. Concentrated the reaction and then added a solution of hydrogen chloride in ethyl acetate. Solid precipitated. Bubbled additional hydrogen chloride through the reaction for thirty minutes and then stirred for three hours. The solid was collected by filtration. Purified using automated flash chromatography with a gradient mobile phase consisting of methanol and dichlorom ethane resulting in the isolation of the hydrochloric salt of 1- benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonic acid piperidin-4-ylamide (2.6 g, 93%).
MS (ESI) m/z 488;
HRMS: calcd for C20H20F3N3O4S2 + H+, 488.09201; found (ESI, [M+H]+), 488.0901;
HPLC purity 100.0% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 2. S-f^lP-^henylsulfonyl^Ctrifluoromethyl^lfl-indol-S- yl]sulfonyl}amino)piperidin-l-yl|sulfonyl}benzoic acid
[0130] To a solution of l-benzenesulfonyM-trifluoromethyl-lH-indole-S-sulfonic acid piperidin-4-ylamide hydrochloride (150 mg, 0.29 mmol) from Example 1, Step 8 and diisopropylethylamine (180 μL, 1.0 mmol) in dichloromethane (8.0 mL) was added 3- (chlorosulfonyl)benzoic acid (69 mg, 0.31 mmol). The reaction was stirred overnight at room temperature. Reaction was washed with 2.0 M hydrochloric acid, dried the organic layer with magnesium sulfate, and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of methanol and dichloromethane resulting in the isolation of the 3-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]sulfonyl}benzoic acid (61 mg, 32 %).
[0131] MS (ES) m/z 671.8;
ΗRMS: calcd for C27H24F3N3O8S3 + H+, 672.07504; found (ESI, [M+H]+), 672.074;
HPLC purity 100.0% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 3. Methyl 4-{[4-({[l-(phenylsulfonyI)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoate
[0132] As in Example 2, l-benzenesulfonyM-trifluoromethyl-lH-indole^-sulfonic acid piperidin-4-ylamide hydrochloride (250 mg, 0.51 mmol) from Example 1, Step 8, terephthalic acid monomethyl ester chloride (112 mg, 0.56 mmol), and diisopropylethylamine (250 μL, 1.8 mmol) in dichloromethane (5.0 mL) provided methyl 4-{[4-({[l-(phenylsulfonyl)- 4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoate (260 mg).
[0133] MS (ES) m/z 649.6;
HRMS: calcd for C29H26F3N3O7S2 + H+, 650.12370; found (ESI, [M+H]+), 650.1224;
HPLC purity 98.2% at 210-370 nm, 10.1 min ; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 4. 4-{[4-({[l-(PhenyIsulfonyl)-4-(trifluoromethyl)-lH-indoI-3- yl|sulfonyl}amino)piperidin-l-yl|carbonyl}benzoic acid
[0134] To a solution of methyl 4-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoate (205 mg, 0.32 mmol) from Example 3 in pyridine (4.0 mL) was added lithium iodide (338 mg, 2.5 mmol). The reaction was
heated to 1000C under nitrogen, overnight. Following day an additional 3 equivalents of lithium iodide was added and the reaction was heated at 1000C for four hours. Reaction was poured onto ammonium chloride solution and extracted with dichloromethane. Dried the organic layer with magnesium sulfate and concentrated. Crude material was purified by reverse phase chromatography with a gradient of water and acetonitrile to give 4-{[4-({[l-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoic acid (41 mg).
[0135] MS (ES) m/z 635.8;
PIRMS: calcd for C28H24F3N3O7S2 + H+, 636.10805; found (ESI, [M+H]+), 636.1057;
HPLC purity 100.0% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 5. Methyl N-{[4-({[l-(phenyIsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl|carbonothioyl}glycinate
[0136] As in Example 2, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonic acid piperidin-4-ylamide hydrochloride (110 mg, 0.21 mmol) from Example 1, Step 8, methyl 2- isothiocyanatoacetate (28 mg, 0.21 mmol), and diisopropylethylamine (55 μL, 0.31 mmol) in dichloromethane (5.0 mL) provided methyl N-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonothioyl}glycinate (29 mg).
[0137] MS (ES) m/z 618.7;
HRMS: calcd for C24H25F3N4O6S3 + H+, 619.09611; found (ESl, [M+H]+), 619.0975;
HPLC purity 100.0% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 6. N-(2-Oxotetrahydrofuran-3-yl)-l-(phenyIsuIfonyl)-4-(trifluoromethyl)-lH- indole- 3-sulfonamide
[0138] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (200 mg, 0.47 mmol) from Example 1, Step 5, alpha-amino-gama- butyrolactone hydrobromide (84 mg, 0.47 mmol), and diisopropylethylamine (247 μL, 1.4 mmol) in dichloromethane (5.0 mL) provided N-(2-oxotetrahydrofuran-3-yl)-l-(phenylsulfonyl)- 4-(trifluoromethyl)-lH-indole- 3-sulfonamide (101 mg).
[0139J MS (ES) m/z 486.9;
HPLC purity 98.4% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 7. 5-Oxo-5-[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl|sulfonyl}amino)piperidin-l-yl]pentanoic acid
[0140] As in Example 2, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonic acid piperidin-4-ylamide hydrochloride (150 mg, 0.31 mmol) from Example 1, Step 8, glutaric anhydride (39 mg, 0.34 mmol), and diisopropylethylamine (60 μL, 0.43 mmol) in
dichloromethane (6.0 mL) provided 5-oxo-5-[4-({[l-(phenylsulfonyl)-4-(trifiuoromethyl)-lH- indol-3- yl]sulfonyl}amino)piperidin-l-yl]pentanoic acid (91 mg).
[0141] MS (ES) m/z 601.8;
HRMS: calcd for C25H26F3N3O7S2 + H\ 602.12370; found (ESI, [M+H]+), 602.1234;
HPLC purity 100% at 210-370 nm, 9.0 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amraon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 8. 4-[2-({[l-(PhenylsulfonyI)-4-(trifluoroinethyl)-lH-indol-3- yl]sιιlfonyl}amino)etliyl]beιizoic acid
[0142] To a solution of 4-(2-aminoethyl)benzoic acid (117 mg, 0.71 mmol) and potassium carbonate (196 mg, 1.42 mmol) in water (5 mL) was added 1 -benzenesulfonyl-4- trifiuoromethyl-lH-indole-3-sulfonyl chloride (300 mg, 0.71 mmol) in acetonitrile (5 mL). The reaction was stirred for five hours and then poured onto 2.0 M hydrochloric acid and extracted with dichloromethane. Dried the organic layer with magnesium sulfate and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of methanol and dichloromethane resulting in the isolation of the 4-[2-({[l- (phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)ethyl]benzoic acid (98 mg).
Example 9. N-ftrans^-AminocyclohexyO-l-tøhenylsulfonyl^-ftrifluoromethyl)-!!!- indole-3- sulfonamide H2
[0143] Step 1. tert-Butyl [trans-4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)cyclohexyl]carbamate
[0144] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (400 mg, 0.94 mmol) from Example 1, Step 5, trans-l,4-diaminocyclohexane (431 mg, 3.8 mmol), di-tert-butyl dicarbonate (823 mg, 3.78 mmol), and diisopropylethylamine (411 μL, 2.4 mmol) in dichloromethane (5.0 mL) provided tert-butyl [trans-4-({[l- (phenylsulfonyl^^tritluoromethyO-lH-indol-S-ylJsulfonyljamino^yclohexy^carbamate (193 mg).
[Ot 4S] MS (ES) m/z 600.0;
HPLC purity 97.2% at 210-370 nm, 10.6 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
H,
[0146J Step 2. N-(trans-4-Aminocyclohexyl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indole-3- sulfonamide
[0147] tert-Butyl [trans-4-({[l-(phenylsulfonyl>4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)cyclohexyl]carbamate (105 mg, 0.17 mmol) was taken up in 6 ml of hydrochloric acid saturated ethyl acetate and the reaction was heated to 600C overnight. Cooled reaction to room temperature and collected the precipitate by filtration giving the hydrochloride salt of N-ftrans^-Aminocyclohexy^-l^phenylsulfonyl^-^fluoromethyO-IH-indole-S- sulfonamide (57 mg).
[0148J MS (ES) m/z 502.0;
HRMS: calcd for C2IH22F3N3O4S2 + H+, 502.10766; found (ESI, [M+H]+), 502.1089;
HPLC purity 100% at 210-370 nm, 7.8 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 10. l-(PhenylsuIfonyl)-N-(tetrahydro-2B-thiopyran-4-yl)-4-(trifluoroinethyl)-lH- indoIe-3-sulfonamide
101501 As in Example 1, Step 6, tetrahydrothiopyran (3.0 g, 26 mmol), 2,4- dimethoxybenzylamine (4.3 g, 26 mmol) , and sodium triacetoxyborohydride (7.7 g, 36 mmol) in dichloromethane (100 mL) provided N-(2,4-dimethoxybenzyl)tetrahydro-2H-thiopyran-4-amine (6.7 g).
[0151] Step 2. N-(2,4-dimethoxybenzyl)-l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4- yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide
[0152] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (500 mg, 1.2 mmol) from Example 1, Step 5, N-(2,4- dimethoxybenzyl)tetrahydro-2H-thiopyran-4-amine (630 mg, 2.4 mmol), and triethyiamine (490 uL, 3.5 mmol) in dichloromethane (25 mL) provided N-(2,4-dimethoχybenzyl)-l- (phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yI)-4-(trifluoromethyl)-lH-indole-3-sulfonamide (720 mg).
[0153] Step 3: l-CPhenylsulfony^-N-Ctetrahydro^H-thiopyran^-yO^^trifluoromethyO-lH- indole-3-sulfonamide
[0154] N-(2,4-dimethoxybenzyl)-l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)- 4-(trifluoromethyl)-lH-indole-3-sulfonamide (720 mg, 1.1 mmol) was dissolved in 6% trifluoroacetic acid/dichloromethane (6 mL) and stirred overnight at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted. Dried with magnesium sulfate and concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)-4-(trifluoromethyl)-lH- indole-3-sulfonamide (500 mg).
[0155] MS (ES) m/z 504.6;
HRMS: calcd for C20H19F3N2O4S3 + H+, 505.05318; found (ESl, [M+H]+), 505.0533;
HPLC purity 100% at 210-370 nm, 10.3 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 11. N-(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsulfoiiyl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide
[0156] l-(Phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)-4-(trifluoromethyl)-lH- indole-3-sulfonamide (90 mg, 0.18 mmol) was dissolved in dichloromethane (8 mL) and 3-
chloroperoxybenzoic acid (88 mg, 0.39 mmol) was added. The reaction was stirred overnight at room temperature and was then concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl )- 1 -(phenyl sulfonyl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide (59 mg).
[0157] MS (ESI) m/z 535;
HRMS: calcd for C20Hi9F3N2O6S3 + H+, 537.04301; found (ESI, [M+H]+), 537.0426;
HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 12. N-(l-oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenyl$ulfonyI)-4- (trifluoromethyl)- lH-indole-3-sulfonamide
[0158] l-(Phenylsulfonyl)-N-(tetiahydiO-2H-thiopyran-4-yl)-4-(lrifluoiOmethyl)-lH- indole-3-sulfonamide (75 mg, 0.15 mmol) was dissolved in dichloromethane (8 mL) and 3- chloroperoxybenzoic acid (37 mg, 0.16 mmol) was added. The reaction was stirred overnight at room temperature and was then concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-(l-oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsulfonyl)-4-(trifluoromethyl)- lH-indole-3-sulfonamide (77 mg).
[0159] MS (ES) m/z 520.5;
HPLC purity 99.4% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 12 trans. trans-N-(l-Oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsulfonyl)-4- (trifluoromethyl)- lH-indoIe-3-sulfonamide
[0160] Separation of N-(l-oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsulfonyl)-4- (trifluoromethyl)- lH-indole-3 -sulfonamide using a prep SFC column 15% methanol/85% CO2 at 50mL/min yielded trans-N-(l-oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsulfonyl)-4- (trifluoromethyl)- lH-indole-3-sulfonamide.
[01611 MS (ES) m/z 520.7;
HRMS: calcd for C20H19F3N2O5S3 + H+, 521.04809; found (ESI, [M+H]+), 521.0488;
HPLC purity 100% at 210-370 nm, 8.6 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 12 cis. cis-N-(l-Oxidotetrahydro-2H-thiopyran-4-yl)-l-(pheiiylsulfonyl)-4- (trifluoromethyl)- lH-indole-3-sulfonamide
[0162] Chiral separation of N-(l-oxidotetrahydro-2H-thiopyran-4-yI)-l- (phenylsulfonyl)-4-(trifluoromethyI)- lH-indole-3-sulfonamide using a prep SFC column 15% methanol/85% CO2 at 50mL/min yielded cis-N-(l-oxidotetrahydro-2H-thiopyran-4-y I)-I- (phenylsulfonyl)-4-(trifiuoromethyl)- lH-indole-3-sulfonamide.
[0163] MS (ES) m/z 520.7;
HRMS: calcd for C20H19F3N2O5S3 + H+, 521.04809; found (ESI, [M+H]+), 521.0479;
HPLC purity 100% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 13. N-(trans-4-HydroxycyclohexyI)-l-(phenylsulfonyI)-4-(trifluoromethyl)-lH- indole- 3-sulfonamide H
[0164] As in Example 8, trans-4aminocyclohexanol (110 mg, 0.94 mmol) and sodium bicarbonate (160 mg, 1.9 mmol) in water (5mL) was combined with l-benzenesulfonyl-4- trifluoromethyl-lH-indole-3-sulfonyl chloride (400 mg, 0.94 mmol) in acetonitrile (5 mL) to provide N-(trans-4-hydroxycyclohexyl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole- 3- sulfonamide (104 mg).
[0165] MS (ES) m/z 502.8;
HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 14. N-(4-Oxocyclohexyl)-l-(phenylsulfonyI)-4-(trifluoromethyl)-lH-indole-3- sulfonamide
[0167] As in Example 1, Step 6, 1,4-cyclohexanedione mono-ethylene ketal (6.0 g, 38 mmol), 2,4-dimethoxybenzylamine (5.8 g, 38 mmol) , and sodium triacetoxyborohydride (11 g, 54 mmol) in dichloromethane (2500 mL) provided N-(2,4-dimethoxybenzyl)-l,4- dioxaspiro[4.5]decan-8-amine (11 g).
[0168] Step 2. N-(2,4-Dimethoxybenzyl)-l-(phenylsulfonyl)-N-(l,4-dioxaspiro[4.5]decan-8- yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide
[0169] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (5.0 g, 12 mmol) from Example 1, Step 5, N-(2,4-dimethoxybenzyl)-l,4- dioxaspiro[4.5]decan-8-amine (5.4 g, 18 mmol), and diisopropylethylamine (5.1 mL, 29 mmol) in dichloromethane (100 mL) provided N-(2,4-dimethoxybenzyl)-l -(phenylsulfonyl)-N-(l, 4- dioxaspiro[4.5]decan-8-yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide (5.4 g).
[0170J Step 3. N-(4κ>xocyclohexyl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide
[0171] N-(2,4-dimethoxyben;.yl)-l-(phenylsulfonyl)-N-(l,4-dioxaspiro[4.5]decan-8- yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide (500 mg, 0.72 mmol) was dissolved in 20% trifluoroacetic acid/dichloromethane (20 mL) and stirred for two days at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted. Dried with magnesium sulfate and concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-(4-oxocyclohexyl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide (500 mg).
[0172] MS (ES) m/z 500.9;
HRMS: calcd for C2IH19F3N2O5S2 + H+, 501.07602; found (ESI, [M+H]+), 501.0769;
HPLC purity 98.5% at 210-370 nm, 9.6 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 15. N-l,4-dioxaspiro[4.5]dec-8-yl-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indole- 3-sulfonamide
[0173] N-(2,4-dimethoxybenzyl)-l -(phenylsulfonyl)-N-(l ,4-dioxaspiro[4.5]decan-8- yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide from Example 14, Step 2 (300 mg, 0.43 mmol) was dissolved in 10% trifluoroacetic acid/dichloromethane (6 mL) and stirred for one day at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted. Dried with magnesium sulfate and concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-l,4-dioxaspiro[4.5]dec-8-yl-l-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indole- 3-sulfonamide (75 mg).
[0174] MS (ES) m/z 544.7;
HRMS: calcd for C23H23F3N2O6S2 + H+, 545.10224; found (ESI, [M+H]+), 545.1028;
HPLC purity 100.0% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 16. l-(Phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-4-(trifluoromethyl)-lH-indoIe-3- sulfonamide
[0175] As in Example 1, Step 7, l-benzenesulfonyl-4-trifiuoromethyl-lH-indole-3- sulfonyl chloride (175 mg, 0.41 mmol) from Example 1, Step 5, 3-(2-aminoethyl)pyridine (55 mg, 0.45 mmol), and diisopropylethylamine (144 μL, 1.0 mmol) in dichloromethane (10 mL) provided l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide (35 mg).
[0176] MS (ES) m/z 510.1;
HRMS: calcd for C22Hi8F3N3O4S2 + H+, 510.07636; found (ESl, [M+H]+), 510.0773;
HPLC purity 91.9% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 17. Methyl oxo[4-({[l-(phenylsuIfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetate
[0177] As in Example 2, l-benzenesulfonyM-trifluoromethyl-lH-indole-S-sulfonic acid piperidin-4-ylamide hydrochloride (325 mg, 0.62 mmol) from Example 1, Step 8, methyl chlorooxoacetate (91 mg, 0.74 mmol), and diisopropylethylamine (220 μL, 1.5 mmol) in dichloromethane (8.0 mL) provided methyl oxo[4-({[l-(phenylsulfonyl)-4-(trifiuoromethyl)-lH- indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetate (206 mg).
10178] MS (ES) m/'z 571.7;
HRMS: calcd for C23H22F3N3O7S2 + H+, 574.09240; found (ESl, [MH-H]+), 574.0908;
HPLC purity 97.8% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 18. Oxo[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetic acid
[0179] To a solution of methyl oxo[4-({[l-(phenylsulfonyi)-4-(trifluoromethyl)-lH- indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetate (120 mg, 0.21 mmol) from Example 3 in pyridine (3.0 mL) was added lithium iodide (196 mg, 1.5 mmol). The reaction was heated to 100
0C under nitrogen, overnight. Reaction was poured onto 2.0 M hydrochloric acid and extracted with dichloromethane. Dried the organic layer with magnesium sulfate and concentrated to give oxo^-dfl-Cphenylsulfonyl^-^rifluoromethylJ-lH-indol-S-yljsulfonyljaminoJpiperidin-l- yl]acetic acid (98 mg).
[0180] MS (ES) m/z 560.0;
ΗPLC purity 100% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 19. l-(Phenylsulfonyl)-iV-(tetrahydro-2JFf-pyran-4-yl)-4-(trifluoromethyl)-l/f- indole-3-sulfonamide
[0181] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (150 mg, 0.35 mmol) from Example 1, Step 6, 4-aminotetrhydropyran hydrochloride (51 mg, 0.37 mmol), and diisopropylethylamine (148 μL, 1.1 mmol) in dichloromethane (8.0 mL) provided l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide (165 mg).
[0182] MS (ES) m/z 489.1;
ΗRMS: calcd for C20H19F3N2O5S2 + H+, 489.07602; found (ESI, [M+H]+), 489.0757;
HPLC purity 89.2% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 20. l-(PhenylsuIfonyl)-iV-(2-pyridin-4-yIethyl)-4-(trifIuoromethyl)-lH-indoIe-3- sulfonamide
[0183] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (500 mg, 1.2 mmol) from Example 1, Step 5, 4-(2-aminoethyl)pyridine (160 mg, 1.3 mmol), and diisopropylethylamine (329 μL, 2.4 mmol) in dichloromethane (15 mL) provided l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide (47 mg).
101841 MS (ES) m/z 509.7;
ΗRMS: calcd for C22Hi8F3N3O4S2 + Η1, 510.07636; found (ESI, [M+H]'), 510.0749;
HPLC purity 100% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 21. l-(Phenylsulfonyl)-iV-(pyridin-3-yImethyl)-4-(trifluoromethyl)-l/f-indole-3- sulfonamide
[0185] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (200 mg, 0.47 mmol) from Example 1, Step 6, 3-(aminomethyl)pyridine (51 mg, 0.47 mmol), and diisopropylethylamine (247 μL, 1.4 mmol) in dichloromethane (8.0 mL) provided l-(phenylsulfonyl)-N-(pyridin-3-ylmethyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide (59 mg).
[0186] MS (ES) m/∑ 495.9;
HRMS: calcd for C21H16F3N3O4S2 + H*, 496.06071; found (ESI, [M+H]'), 496.0613; HPLC purity 100.0% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amraon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 22. l-(Phenylsulfonyl)-Λ/-pyrroIi(lin-3-yl-4-(trifluoromethyl)-lf/-indθle-3- sulfonamide
[0187] Step 1. tcrt-Butyl 3-(l-(phenylsulfonyl)-4-(trifluoromcthyl)-lH-indole-3- sulfonamido)pyrrolidine-l-carboxylate
[0188] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (190 mg, 0.44 mmol) from Example 1, Step 5, l-Boc-3-aminopyrrolidine (100 mg, 0.54 mmol), and diisopropylethylamine (156 μL, 1.1 mmol) in dichloromethane (4.0 mL) provided tert-butyl 3-(l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamido)pyrrolidine-l-carboxylate (104 mg).
[0189] Step 2. l-CPhenylsulfonyO-N-pyrrolidin-S-yl^-CtrifluoromethyO-lH-indole-S- sulfonamide
[01901 tcrt-Butyl 3-(l-(phcnylsulfonyl)-4-(trifluoromcthyl)-lH-indolc-3- sulfonamido)pyrrolidine-l-carboxylate (100 mg, 0.17 mmol) was dissolved ethanol (2.0 mL) and 4.0 M hydrochloric acid in dioxane (0.50 mL) was added. The reaction was heated to 600C for four hours and then cooled reaction to room temperature and collected the precipitate by filtration giving the hydrochloride salt of l-(phenylsulfonyl)-JV-pyrrolidin-3-yl-4- (trifiuoromethyl)-lH-indole-3-sulfonarnide (95 mg).
[01911 MS (ES) m/∑ 473.7;
ΗRMS: calcd for C)9H18F3N3O4S2 + H+, 474.07636; found (ESI, [M+H]+), 474.0763;
HPLC purity 100% at 210-370 nm, 7.7 min.; Xterra RP18, 3. Su, 150 x 4.6 mm column, 1 2 mL/min, 85/15-5/95 (Λmmon. Form. Buff. Ph=3.5/ΛCN+MeOH) for lOmin, hold 4min.
Example 23. l-(phenylsulfonyl)-yV-(pyridin-4-ylniethyl)-4-(trifluoroniethyl)-lH-indole-3- sulfonamide
[0192| As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lΗ-indole-3- sulfonyl chloride (250 mg, 0.59 mmol) from Example 1, Step 5, 4-(aminomethyl)pyridine (69 uL, 0.68 mmol), and triethylamine (206 μL, 1.5 mmol) in dichloromethane (6.0 mL) provided 1- (phenylsulfonyl)-N-(pyridin-4-ylmethyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide (51 mg).
[0193] MS (ES) m/z 495.8;
HPLC purity 92.1% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 24. l-(phenylsulfonyl)-ΛL(tetrahydro-2//rpyran-4-yImethyl)-4-(trifluoromethyl)- lH-indole-3-sulfonamide
[0194] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (150 mg, 0.35 mmol) from Example 1, Step 5, 4-(aminomethyl)tetrahyropyran (41 mg, 0.35 mmol), and morpholinomethyl polystyrene (700 mg, excess) in dichloromethane (5.0 mL) provided l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-4-(trifluoromethyl)- lH-indole-3-sulfonamide (64 mg).
[0195] MS (ES) m/z 502.8;
ΗPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 25. l-(phenylsulfonyl)-Λr-(2-pyridin-2-ylethyl)-4-(trifIuoromethyl)-ljRr-indole-3- sulfonamide
[0196] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (200 mg, 0.47 mmol) from Example 1, Step 5, 2-(2-aminoethyl)pyridine (69 mg, 0.57 mmol), and triethylamine (164 μL, 1.2 mmol) in dichloromethane (4.0 mL) provided 1-
(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-4-(trifluororaethyl)-lH-indole-3-sulfonamide (45 mg).
[0197] MS (ES) m/z 510.1;
ΗRMS: calcd for C22H18F3N3O4S2 + H+, 510.07636; found (ESl, [M+H]+), 510.0761;
HPLC purity 89.6% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 26. terf-Butyl 4-({[l-(phenylsulfonyl)-4-(tiifluoromethyI)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate
[0198] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lΗ-indole-3- sulfonyl chloride (500 mg, 1.2 mmol) from Example 1, Step 5, 4-amino-l-Boc-piperidine (284 mg, 1.4 mmol), and triethylamine (411 μL, 2.6 mmol) in dichloromethane (75 mL) provided tert- butyl 4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate (640 mg).
[0199] MS (ES) nv'z 586.1;
ΗRMS: calcd for C25H28F3N3O6S2 + H+, 588.14444; found (ESI, [M+H]+), 588.1437;
HPLC purity 100% at 210-370 nm, 10.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 27. N-[(3/f)-l-Benzylpyrrolidin-3-yl]-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indole-3-sulfonamide
[0200] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (300 mg, 0.71 mmol) from Example 1, Step 5, 3R-(-)-l-benzyl-3- aminopyrrolidine (130 mg, 0.71 mmol), and diisopropylethylamine (250 μL, 1.4 mmol) in dichloromethane (4.0 mL) provided N-[(3/?)-l-benzylpyrrolidin-3-yl]-l-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide (96 mg).
(0201] MS (ES) m/z 564.0;
ΗRMS: calcd for C26H24F3N3O4S2 + H+, 564.12331; found (ESl, [NHH]+), 564.1254;
HPLC purity 100% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 28. tert-Butyl [trans-4-({ll-(phenylsulfonyl)-4-(trifluoroniethyl)-lH-indol-3- yl]sιιlfonyl}amino)cyclohexyl] carbamate
[0202] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (400 mg, 0.94 mmol) from Example 1, Step 6, trans- 1,4-diaminocyclohexane (431 mg, 3.8 mmol), di-tert-butyl dicarbonate (823 mg, 3.78 mmol), and diisopropylethylamine (411 μL, 2.4 mmol) in dichloromethane (5.0 mL) provided tert-butyl [trans-4-({[l- (phenylsulfonyl)-4-(trifluoromethyl)- 1 H-indol-3-yl]sulfonyl }amino)cyclohexyl]carbamate (193 mg).
[0203| MS (ES) m/z 600.0;
HPLC purity 97.2% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1 2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 29. 4-{[3-[(Piperidin-4-ylamino)sulfonyl]-4-(trifluoromethyl)-lH-indoI-l- yljsulfonyl} benzoic acid
[0204J Step 1. før*-Butyl 4-({[4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate
[0205] To a solution of terr-butyl 4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol- 3-yl]sulfonyl}amino)piperidine-l-carboxylate (200 mg, 0.34 mmol) from Example 26 in dimethylformamide (3.0 mL) at room temperature was added pyridine (69 μL, 0.85 mmol). The reaction was stirred under nitrogen at room temperature overnight. Then benzylamine (36 mg,
0.34 mmol) was added and the reaction was stirred for four hours and then heated to 500C overnight. Poured reaction onto water and extracted with dichloromethane, dried the organic layer with magnesium sulfate, and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of tert-butyl 4-({[4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}arnino)piperidine-l- carboxylate (150 mg ).
[0206] MS (ES) m/z 445.8;
ΗPLC purity 98.4% at 210-370 nm, 9.3 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
[0207] Step 2. 4-(3-(N-(l-(tert-Butoxycarbonyl)piperidin-4-yl)sulfamoyl)-4-(trifluoromethyl)- lH-indol-l-ylsulfonyl)benzoic acid
[0208] To a solution of ter/-butyl 4-({[4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate (180 mg, 0.39 mmol), triethylamine (140 μL, 0.98 mmol), and N,N-dimethylarninopyridine (10 mg, catalytic) in dichloromethane (10 mL) under nitrogen was added 2-pyridinesulfonyl chloride hydrochloride (92 mg, 0.43 mmol). The reaction was stirred overnight at room temperature and then poured onto aqueous ammonium chloride and extracted. Dried the organic layer with magnesium sulfate and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 4-(3-(N-(l-(tert-butoxycarbonyl)piperidin-4- yl)sulfamoyl)-4-(trifluoromethyl)-lΗ-indol-l-ylsulfonyl)benzoic acid (186 mg).
[0209] Step 3. 4-{[3-[(piperidin-4-ylamino)sulfonyl]-4-(trifluoromethyl)-lH-indol-l- yl]sulfonyl}benzoic acid
[0210] As in Example 9, Step 2 4-(3-(N-(I -(tert-butoxycarbonyl)piperidin-4- yl)sulfamoyl)-4-(trifluoromethyl)-lH-indol-l-ylsulfonyl)benzoic acid (150 mg, 0.17 mmol) in hydrochloric saturated ethyl acetate (8.0 mL) at 60 0C provided the hydrochloride salt of 4-{[3- [(piperidin-4-ylamino)sulfonyl]-4-(trifluoromethyl)-lH-indol-l-yl]sulfonyl}benzoic acid (120 mg)
MS (ES) m/z 531.7.
Example 30. S-ttϊl-CPhenylsuIfony^-Ctriπuoroinethyl^lM-indoI-S- yljsulfonyl}amino)propaιie-l-sιilfoiiic acid
[0211] As in Example 8, 3-Amino-l-propanesulfonic acid (130 mg, 0.92 mmol) and potassium carbonate (196 mg, 1.4 mmol) in water (6 mL) was combined with 1- benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl chloride (300 mg, 0.92 mmol) in acetonitrile (6 mL) provided 3-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)propane-l-sulfonic acid (37 mg).
[0212] MS (ES) m/z 525.0;
HPLC purity 98.3% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 31. l-(Phenylsulfonyl)-7V-(2,2,6,6-tetramethylpiperidin-4-yl)-4-(trinuoromethyI)- lH-indole-3-sulfonamide
[0213] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lΗ-indole-3- sulfonyl chloride (225 mg, 0.53 mmol) from Example 1, Step 6, 4-amino-2,2,6,6- tetramethylpiperidine (100 mg, 0.64 mmol), and triethylamine (185 μL, 1.3 mmol) in dichloromethane (5.0 mL) provided 1-(phenylsulfonyl)-Λ/"-(2,2,6,6-tetramethy1piperidin-4-yl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide (37 mg).
[0214] MS (ES) m/z 543.7;
ΗRMS: calcd for C24H28F3N3O4S2 + H+, 544.15461; found (ESI, [M+H]+), 544.1528;
HPLC purity 99.2% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. Ph=9.5/ACN+MeOH) for lOmin, hold 4min.
Example 32. N-CyclohexyI-l-(phenylsuIfonyl)-4-(trifluoromethyl)-lJc-r-indole-3- sulfonamide
[0215] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (200 mg, 0.47 mmol) from Example 1, Step 5, cyclohexylamine (47 mg, 0.47 mmol), and diisopropylethylamine (247 μL, 1.4 mmol) in dichloromethane (8.0 mL) provided N- cyclohexyl-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide (100 mg).
[0216] MS (ES) m/z 486.9,
ΗPLC purity 97.1% at 210-370 nm, 20.7 min.; XTerra MS C18 3xl50mm column, 0.5 mL/min, formic acid / MeOH 20min grad.
Example 33. N-[2-(l//-Benzimidazol-2-yl)ethyl]-l-(phenylsuIfonyl)-4-(trifluoromethyl)-l//- indole-3-suIfonamide
[0217] As in Example 1, Step 7, l-benzenesulfonyl-4-trifluoromethyl-lΗ-indole-3- sulfonyl chloride (200 mg, 0.47 mmol) from Example 1 , Step 5, 2-(2-aminoethyl)benzimidazole hydrochloride (47 mg, 0.47 mmol), and diisopropylethylamine (247 μL, 1.4 mmol) in dichloromethane (8.0 mL) provided N-[2-(lH-benzimidazol-2-yl)ethyl]-l-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide (68 mg).
[0218] MS (ES) m/z 549.0;
ΗRMS: calcd for C24Hi9F3N4O4S2 + H+, 549.08726; found (ESI, [M+Hf), 549.0881;
HPLC purity 100% at 210-370 nm, 8.8 min.; XterraRP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 34. 5-[4-({[4-isopropyI-l-(phenylsulfonyl)-l//-indol-3- yl]sulfonyl}amino)piperidin-l-yl]-5-oxopentanoic acid
[0219] Step 1. l-(Phenylsulfonyl)-lH-pyrrole
[0220] To a solution of 2,5-dimethoxytetrahydrofuran (8.7 mL, 67 mmol) in water (30 mL) was added portion wise benzene sulfonamide (7.0 g, 45 mmol). The solution was heated with stirring using microwave irradiation (1400C) for 25 minutes. After cooling to room temperature the reaction was filtered and the crude product was taken up in dichloromethane and filtered through a plug of silica gel to give l-(phenylsulfonyl)-lH-pyrrole (9.6 g).
[0221] Step 2. 2-Methyl-l-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one
[0222] To a slurry of aluminum chloride (6.6 g, 49 mmol) in dichloroethane (125 mL) at 0 0C, was added isobutyryl chloride (4.8 g, 45 mmol) dropwisc over thirty minutes. The
reaction was stirred at 00C for twenty minutes, at which time a solution had formed. Then 1- (phenylsulfonyl)-lH-pyrrole (8.5 g, 41 mmol) was added portion wise. The reaction was stirred at room temperature overnight, and then poured onto ice/water and extracted. Washed with saturated ammonium chloride, dried organic layer with magnesium sulfate, and concentrated. The crude residue was purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 2-methyl-l-(l- (phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one (1O g, 90%).
[0223] Step 3. l-(l,3-Dioxan-2-yl)-4-methyl-3-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)pentan-3- ol
[0224] To a slurry of cerium chloride (13.6 g, 55.1 mmol) in tetrahydrofuran (300 mL) at 0 0C was added (l,3-dioxan-2ylethyl)magnesium bromide (27.6 mL, 55.1 mmol). The reaction was stirred at 0 0C for thirty minutes and then 2-methyl-1-(1-(phenylsulfonyl)-1H- pyrrol-3-yl)propan-l-one (10.2 g 36.8 mmol) was added portion wise. The reaction was stirred for three hours and then poured onto ice/water and extracted with ethyl acetate. Washed with saturated sodium bicarbonate solution and water, dried with magnesium sulfate, and concentrated to give l-(l,3-dioxan-2-yl)-4-methyl-3-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)pentan- 3-ol (19.0 g, 98%).
[0225] Step 4. 4-Isopropyl-l-(phenylsulfonyl)-lH-indole
[0226] l-Cl^-dioxan^-yO^-methyl-S-Cl-CphenylsulfonyO-lH-pyrrol-S-yOpentan-S-ol (14 g, 36 mmol) was dissolved in 6% sulfuric acid/ethanol and heated under nitrogen for one hour and then stirred at room temperature overnight. The reaction was poured onto ice/water and extracted with ethyl acetate. Washed with saturated sodium bicarbonate solution, dried with magnesium sulfate, and concentrated to give 4-isopropyl-l-(phenylsulfonyl)-lH-indole (9.4 g,
[0227] Step 5. 4-lsopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid
[0228] As in Example 1, Step 4, 4-isopropyl-l-(phenylsulfonyl)-lH-indole (9.4 g, 31 mmol) and chlorosulfonic acid (2.2 mL, 33 mmol) in dichloromethane (200 mL) at 00C provided 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid (12 g, crude).
[0229] Step 6. 4-Isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride
[0230] As in Example 1, Step 5, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid (12 g, 31 mmol) and phosphorus pentachloride (2.5 g, 12 mmol) in phosphorus oxychloride (25 mL) was heated to 1000C for five hours to give 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3- sulfonyl chloride (4.3 g).
[0231] Step 7. 5-[4-({[4-Isopropyl-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]-5-oxopentanoic acid
[0232] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (150 mg, 0.30 mmol), glutaric anhydride (38 mg, 0.33 mmol), and triethylamine (84 μL, 0.60 mmol) in dichloromethane (6.0 mL) provided 5-[4-({[4-isopropyl-l-(phenylsulfonyl)-lH- indol-3-yl]sulfonyl}amino)piperidin-l-yl]-5-oxopentanoic acid (136 mg).
MS (ES) m/z 575.8;
ΗRMS: calcd for C27H33N3O7S2 + H+, 576.18327; found (ESI, [M+H]+), 576.1824;
HPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 35. iV-(frfl«5-4-HydroxycyclohexyI)-4-isopropyI-l-(phenylsulfonyl)-lH-indoIe-3- sulfonamide
[0233] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (250 mg, 0.63 mmol) from Example 34, Step 6, trans-4-aminocyclohexanol, (87 mg, 0.75 mmol), and triethylamine (274 μL, 1.6 mmol) in dichloromethane (6.0 mL) provided N-(//W75-4-hydroxycyclohexyl)-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (142 mg).
[0234] MS (ES) m/z 477.0;
HRMS: calcd for C23H28N2O5S2 + H', 477.15124; found (ESI, [M+H]f), 477.1522; HPLC purity 91.9% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 36, te/tf-Butyl 4-({[4-isopropyl-l-(phenylsulfonyl)-l J/-indol-3- yl|sulfonyl{aniino)piperidine-l-carboxylate
[0235] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (500 mg, 1.3 mmol) from Example 34, Step 6, 4-amino-l-Boc-piperidine (300 mg, 1.5 mmol), and triethylamine (440 μL, 3.1 mmol) in dichloromethane (50 mL) provided 4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate (650 mg).
[0236] MS (ES) m/∑ 560.2;
ΗPLC purity 100% at 210-370 nm, 11.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 37. 4-Isopropyl-l-(phenylsulfonyl)-Λ'-piperidin-4-yl-l/ϊ-indole-3-sulfonamide
[0237] As in Example 9, Step 2 tørf-butyl 4-({ [4-i sopropy 1-1 -(phenyl sulfony I)- IH- indol-3-yl]sulfonyl}amino)piperidine-l-carboxylate (1.9 g, 3.4 mmol) from Example 36, in
hydrochloric saturated ethyl acetate (75 mL) provided the hydrochloride salt of 4-isopropyl-l- (phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (360 mg).
[0238] MS (ES) m/z 462.0;
ΗRMS: calcd for C22H27N3O4S2 + Η\ 462.15157; found (ESI, [M+H]1), 462.1495;
HPLC purity 100% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 38. 3-{[4-({[4-Isopropyl-l-(phenylsulfonyl)-lH-indol-3- yl]sυlfonyl}amiiio)piperidiii-l-yl]sulfonyl}benzoic acid
[0239] As in Example 2, 4~isopropyl-l-(phenylsulfonyl)-iV-piperidin-4-yl-lH-indole-3- sulfonamide hydrochloride (300 mg, 0.60 mmol) from Example 37, 3-(chlorosulfonyl)benzoic acid (133 mg, 0.60 mmol), and triethylamine (336 μL, 12.4 mmol) in dichloromethane (6.0 mL) provided 3-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid (43 mg).
[0240] MS (ES) m/z 645.8;
ΗRMS: calcd for C29H3IN3O8S3 + H+, 646.13460; found (ESI, [M+H]+), 646.1335;
HPLC purity 100% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 39. 4-{[4-({[4-Isopropyl-l-(phenylsulfonyl)-17/-indol-3- yl]sulfonyl}amino)piperidin-l-yl]sulfonyl}benzoic acid
[0241] As in Example 2, 4-isopropyl-l-(phenylsulfonyI)-N-piperidin-4-yl-lH-indole-3- sulfonamide hydrochloride (300 mg, 0.60 mmol) from Example 37, 4-(chlorosulfonyl)benzoic acid (133 mg, 0.60 mmol), and triethylamine (336 μL, 12.4 mmol) in dichloromethane (6.0 mL) provided 4-{[4-({ [4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid (150 mg).
[0242] MS (ES) m/z 645.8;
ΗRMS: calcd for C29H31N3O8S3 + H+, 646.13460; found (ESI, [M+HJ"), 646.1317;
HPLC purity 100% at 210-370 nm, 10.2 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 40. 4-Isopropyl-l-(phenyIsuIfonyI)-yV-(2-pyridin-4-ylethyl)-lH-indole-3- sulfonamide
[0243] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sιιlfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, 4-(2-aminoethyl)pyridine (30 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL)
provided 4-isopropyl-l -(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide (69 mg)-
[0244] MS (ES) m/∑ 481.9;
ΗRMS: calcd for C24H25N3O4S2 + H*, 484.13592; found (ESI, [M+H]f), 484.1365; HPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 41. 4-Isopropyl-l-(phenylsuIfonyl)-N-(tetrahydro-2f/-thiopyran-4-yl)-l//-indole- 3-sulfonaniide
[0245] As in Example 10, Step 3, N-(2,4-dimethoxybenzyl)-l-(phenylsulfonyl)-N- (tetrahydro-2H-thiopyran-4-yl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide (500 mg, 1.3 mmol) in 6 % trifiuoroacetic acid/dichloromethane (6.0 niL) provided 4-isopropyl-l- (phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)-lH-indole-3-sulfonamide (490 mg).
[0246] MS (ES) m/z 476.6;
ΗRMS: calcd for C22H26N2O4S3 + H+, 479.11274; found (ESI, [M+H]+), 479.1 14;
ILPLC purity 100% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 42. 7V-(l,l-Dioxidotetrahydro-2/f-thiopyran-4-yl)-4-isopropyI-l-(phenylsulfonyl)- lH-indole-3-suIfonaniide
[0247| As in Example 11, 4-isopropyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran- 4-yl)-lH-indole-3-sυlfonamide (80mg, 0.17 mmol) and 3-chloroperoxybenzoic acid (82 mg, 0.37 mmol) in dichloromethane provided N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-4-isopropyl-l- (phenylsulfonyl)-lH-indole-3-sulfonamide (43 rag).
[0248] MS (ES) m/z 508.7;
ΗPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACΝ+MeOΗ) for lOmin, hold 4min.
Example 43. 4-Isopropyl-Λ/-(l-oxidotetrahydro-2//-thiopyran-4-yl)-l-(phenylsuIfonyI)-l/f- indole-3-sulfonaniide
[0249] As in Example 12, 4-isopropyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran- 4-yl)-lH-indole-3-sulfonamide (112 mg, 0.23 mmol) and 3-chloroperoxybenzoic acid (55 mg, 0.25 mmol) in dichloromethane (2.0 mL) provided 4-isopropyl-N-(l-oxidotetrahydro-2H- thiopyran-4-yl)-l -(phenylsulfonyl)-lH-indole-3-sulfonamide (86 mg).
[0250] MS (ES) m/z 494.7;
IERMS: calcd for C22H26N2O5S3 + H+, 495.10766; found (ESI, [MHI]+), 495.1064;
HPLC purity 100% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 44. 4-Isopropyl-l-(phenylsulfonyl)-/V-(2-pyridin-3-ylethyI)-l//-indole-3- sulfonamide
[0251J As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, 3-(2-aminoethyl)pyridine (30 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided 4-isopropyl-l -(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonarnide (69 mg).
[0252] MS (ES) m/z 481.9;
ΗRMS: calcd for C24H25N3O4S2 + H+, 484.13592; found (ESI, [M+H]4), 484.1365;
HPLC purity 100% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 45. /V-[3-(l//-Imidazol-l-yl)propylJ-4-isopropyl-l-(phenylsulfonyl)-l/f-indole-3- suifonamide
[0253] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, l-(3-aminppropyl)-imidazole (30 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 nig, excess) in dichloromethane (8.0 mL) provided N-[3-(lH-imi dazol-l-yl)propyl]-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3- sulfonamide (32 mg).
[02541 MS (ES) m/z 485.1;
ΗRMS: calcd for C23H26N4O4S2 + H+, 487.14682; found (ESI, [M+H]+), 487.1472;
HPLC purity 96.9% at 210-370 nm, 8.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 46. 4-IsopropyI-N-(2-morphoIin-4-ylethyl)-l-(phenylsulfonyl)-l//-indole-3- sulfonamide
[0255] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, 4-(2-aminoethyl)morpholine (33 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided 4-isopropyl-Λr-(2-moφholin-4-ylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (77 mg).
[0256] MS (ES) m/z 489.9;
ΗRMS: calcd for C23H29N3O5S2 + H+, 492.16214; found (ESl, [M+H]+), 492.1627;
HPLC purity 99.5% at 210-370 nm, 9.0 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 47. 4-isopropyl-yV-(2-phenylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide
[0257J As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, phenethylamine (31 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided 4- isopropyl-N-(2-phenylethyl)-l-(phenylsuIfonyl)-lH-indole-3-sulfonamide (71 mg).
[0258] MS (ES) m/z 481.1;
ΗRMS: calcd for C25H26N2O4S2 + H+, 483.14067; found (ESl, [M+H]+), 483.1410;
HPLC purity 98.8% at 210-370 nm, 11.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 48. 4-Isopropyl-l-(phenylsuIfonyl)-Λ'-(tetrahydro-2//-pyran-4-yI)-lH-indole-3- sulfonamide
[0259] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, 4-aminotetrahydropyran hydrochloride (25 mg, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided 4-isopropyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- sulfonamide (130 mg).
[0260] MS (ES) m/z 460.9;
HRMS: calcd for C22H26N2O5S2 + H* , 463.13559; found (ESI, [M+H]f), 463.1361; HPLC purity 100% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amraon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 49. Ethyl 4-({[4-isopropyl-l-(phenylsulfonyl)-lAf-indθI-3- yl]sulfonyl}amino)piperidine-l-carboxylate
[0261] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, ethyl 4-amino-l-piperidine-carboxylate (43 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 niL) provided ethyl 4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate (107 mg).
[0262] MS (ES) m/z 531.9,
ΗRMS: calcd for C25H3IN3O6S2 + H+, 534.17270; found (ESI, [M+H]+), 534.1733;
HPLC purity 100% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 50. 4-Isopropyl-l-(phenylsulfonyl)-Λ'-(2-pyridin-2-ylethyl)-l/-r-indole-3- sulfonamide
[0263] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, 2-(2-aminoethyl)pyridine (30 μL, 0.25 mmol), and moφholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided 4-isopropyl-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide (150 mg).
[0264] MS (ES) m/z 481.9;
ΗRMS: calcd for C24H25N3O4S2 + H+, 484.13592; found (ESI, [MH-H]+), 484.1358;
HPLC purity 100% at 210-370 nm, 10.2 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 51. 4-IsopropyI-l-(phenylsulfonyl)-N-[2-(tetrahydro-2//-pyran-4-yl)ethyl]-l//- indoIe-3-sulfonam ide
10265] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (150 mg, 0.38 mmol) from Example 34, Step 6, 4-(2-aminoethyl)tetrahydropyran (49 mg, 0.38 mmol), and moφholinomethyl-polystyrene (500 mg, excess) in dichloromethane (4.0 mL) provided 4-isopropyl-l-(phenylsulfonyl)-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-lH-indole- 3-sulfonamide (110 mg).
[0266J MS (ESI) m/z 489;
HRMS: calcd for C24H30N2O5S2 + H\ 491.16689; found (ESI, [M+H]+), 491.1658; HPLC purity 93.5% at 210-370 nm, 10.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 52, 4-Isopropyl-1-(phenylsulfonyl)-jV-(tetrahydro-2f/-pyran-4-ylmethyl)-lf/- indole-3-sulfonamide
|0267J As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (150 mg, 0.38 mmol) from Example 34, Step 6, 4-aminomethyltetrahydropyran (43 mg, 0.38 mmol), and morpholinomethyl-polystyrene (500 mg, excess) in dichloromethane (4.0 mL) 4-i sopropyl- 1 -(phenyl sulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)- lH-indole-3-sulfonamide (120 mg).
10268J MS (ES) m/z 475.1 ;
ΗRMS: calcd for C23H28N2O3S2 + H+, 477.15124; found (ESI, [M+H]+), 477.1518;
HPLC purity 100% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example S3. Λr-Benzyl-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonamide
[0269] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, benzylamine (27 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided N- benzyl-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (35 mg).
[0270] MS (ES) m/z 467.1;
ΗRMS: calcd for C24H24N2O4S2 + Na+, 491.10697; found (ESI, [M+Na]*), 491.1078;
HPLC purity 100% at 210-370 nm, 10.9 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 πiL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 54. 4-lsopropyl-N-(3-phenylpropyl)-l-(phenylsulfonyl)-lH-indole-3-suIfonamide
[0271] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (100 mg, 0.25 mmol) from Example 34, Step 6, 3-phenyl-l-propylamine (36 μL, 0.25 mmol), and morpholinomethyl-polystyrene (200 mg, excess) in dichloromethane (8.0 mL) provided 4-isopropyl-N-(3-phenylpropyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (56 mg).
[0272] MS (ES) m/z 495.1 ;
ΗRMS: calcd for C26H28N2O4S2 + H+, 497.15632; found (ESI, [M^-H]+), 497.1568;
HPLC purity 100% at 210-370 nm, 11.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 55. 3-({[4-({[4-Isopropyl-l-(phenylsulfonyI)-lJΪ-indol-3- yl]sulfonyl}amino)piperidin-l-yl|carbonothioyl}amino)benzoic acid
[0273] As in Example 2, 4-isopropyl-l-(phenylsulfonyl)-Λf-piperidin-4-yl-lH-indole-3- sulfonamide hydrochloride (100 mg, 0.20 mmol) from Example 37, 3-carboxyphenylisocyanate (45 mg, 0.20 mmol), and triethylamine (55 μL, 0.40 mmol) in dichloromethane (4.0 mL) provided 3-({[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]carbonothioyl}amino)benzoic acid (34 mg).
[0274] MS (ES) m/z 641.1;
ΗPLC purity 98.2% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 56. iV-(2-Hydroxy-2-pyridin-3-ylethyl)-4-isopropyl-l-(phenylsulfonyl)-l/ir-indole- 3-sulfonamide
[0275] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (200 mg, 0.50 mmol) from Example 34, Step 6, 2-amino-l-(pyridin-3-yl)ethanol (119 mg, 0.60 mmol), and triethylamine (210 μL, 1.5 mmol) in dichloromethane (8.0 mL) provided
N-(2-hydroxy-2-pyridin-3-ylethyl)-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (36
mg).
[0276] MS (ES) m/z 418.1;
HRMS: calcd for C24H25N3O5S2 + H+, 500.13084; found (ESl, [M+H]+), 500.13;
HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 57. 4-Iisopropyl-l-(phenylsulfonyl)-ΛT-(2-thiomorpholin-4-yIethyI)-l//-indole-3- sulfonamide
[0277] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (450 mg, 1.1 mmol) from Example 34, Step 6, 4-(2-aminoethyl)thiomorpholine (180 mg, 1.2 mmol), and triethyiamine (390 μL, 1.5 mmol) in dichloromethane (10 mL) provided 4- isopropyl-1 -(phenylsulfonyl)-N-(2-thiomoφholin-4-ylethyl)-lH-indole-3-sulfonamide (36 mg).
[0278] MS (ES) m/z 507.7;
ΗRMS: calcd for C23H29N3O4S3 + H+, 508.13929; found (ESI, [MH-H]+), 508.1399;
HPLC purity 98.3% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 58. 4-Isopropyl-N-(l-methylpiperidin-4-yl)-l-(phenyIsulfonyl)-lH-indoIe-3- sulfonamide
[0280] As in Example 1, Step 6, l-methyl-4-piperidone (1.3 g, 11 mmol), 2,4- dimethoxybenzylamine (1.7 mL, 11 mmol) , and sodium triacetoxyborohydride (3.3 g, 16 mmol) in dichloromethane (100 mL) provided N-(2,4-dimethoxybenzyl)-l-methylpiperidin-4-amine (2.8 g).
[0281] Step 2. N-(2,4-Dimethoxybenzyl)-4-isopropyl-N-(l-methylpiperidin-4-yl)-l- (phenylsulfonyl)-lH-indole-3-sulfonamide
[0282] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (300 mg, 0.75 mmol) from Example 34, Step 6, N-(2,4-dimethoxybenzyl)-l- methylpiperidin-4-amine (400 mg, 1.5 mmol), and diisopropylethylamine (330 μL, 1.9 mmol) in dichloromethane (10 mL) provided N-(2,4-dimethoxybenzyl)-4-isopropyl-N-(l-methylpiperidin- 4-yl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (215 mg).
[0283] Step 3. 4-lsopropyl-N-(l-methylpiperidin-4-yl)-l-(phenylsulfonyl)-lH-indole-3- sulfonamide
[0284] As in Example 1, Step 8, N-(2,4-Dimethoxybenzyl)-4-isopropyl-N-(l- methylpiperidin-4-yl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (500 mg, 0.72 mmol) was dissolved in 20% trifluoroacetic acid/dichloromethane (8.0 mL) to provide 4-isopropyl-N-(l- methylpiperidin-4-yl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (120 mg).
[0285] MS (ES) m/z 476.1 ;
HRMS: calcd for C23H29N3CMS2 + H+, 476.16722; found (EST, [M+H]+), 476.1665;
HPLC purity 100.0% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 59. Methyl 4-{[4-({[4-isopropyl-l-(phenylsulfonyl)-l//-indol-3- yl]suiroιiyl}aiiiino)piperidiii-l-yl]carboiiyl}benzoale
[0286] As in Example 2, 4-isopropyl-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3- sulfonamide hydrochloride (300 mg, 0.60 mmol) from Example 37, terephthalic acid monomethyl ester chloride (130 mg, 0.66 mmol), and triethylamine (290 μL, 2.1 mmol) in dichloromethane (4.0 mL) provided methyl 4-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoate (250 mg).
[0287J MS (ES) m/z 623.8;
HRMS: calcd for C3IH33N3O7S2 + H+, 624.18327; found (ESI, [M+H]+), 624.1799; HPLC purity 100% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 60. 4-Bromo-1-(phenylsulfonyl)-yV-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide
[0288] Step 1. l-Benzenesulfonyl-4-bromo-lH-indole
[0289] As in Example 1, Step 3, 4-bromoindole (3.0 niL, 10 mmol), 60 % sodium hydride (1.0 g, 24 mmol) benzenesulfonyl chloride (3.6 mL, 15 mmol) in dimethylformamide (200 mL) provided l-benzenesulfonyl-4-bromo-lH-indole (6.6 g)
[0290] Step 2. l-BenzenesulfonyM-bromo-lH-indole-S-sulfonic acid
[0291] As in Example 1, Step 4, l-benzenesulfonyl-4-bromo-lH-indole (6.6 g, 20 mmol) and chlorosulfonic acid (1.3 mL, 20 mmol) in dichloromethane (100 mL) provided 1- benzenesulfonyl-4-bromo-lH-indo!e-3-sulfonic acid (8.2 g crude).
[0292] Step 3. l-Benzenesulfonyl-4-bromo-lH-indole-3-sulfonyl chloride
[0293] As in Example 1, Step 5, l-benzenesulfonyM-bromo-lH-indole-S-sulfonic acid (8.2 g, 20 mmol) and phosphorus pentachloride (6.1 g, 30 mmol) in phosphorus oxychloride (30 mL) provided l-benzenesulfonyl-4-bromo-lH-indole-3-sulfonyl chloride (6.7 g).
[0294] Step 4. 4-Bromo-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide
[0295] As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (540 mg, 1.2 mmol), 3-(2-aminoethyl)pyridine (167 mg, 1.4 mmol), and triethylamine (364 L, 2.6 mmol) in dichloromethane (10 mL) provided 4-bromo-l-(phenylsulfonyl)-N-(2- pyridin-3-ylethyl)-lH-indole-3-sulfonamide (45 mg).
[0296] MS (ESI) m/z 520;
HPLC purity 99.0% at 210-370 nm, 8.9 min.; 99.6% at 262 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 61. tert-Buty\ 4-({[4-bromo-l-(phenylsulfonyl)-l//-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate
[0297J As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (1.0 g, 2.3 mmol) from Example 60, Step 3, 4-amino-l-Boc-piperidine (0.55 g, 2.8 mmol), and triethylamine (0.64 mL, 4.6 mmol) in dichloromethane (25 mL) provided tert-butyl 4-({[4-bromo-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l-carboxylate (l. l g)-
10298] MS (ES) m/z 596.0,
HRMS: calcd for C24H28BrN3O6S2 + H+, 598.06756; found (ESI, [M+H]+), 598.0705; HPLC purity 85.1% at 210-370 nm, 10.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.
Example 62. 4-Bromo-l-(phenylsulfonyl)-Λr-piperidin-4-yl-l//-indole-3-su]fonamide
[0299] As in Example 9, Step 2 tert-butyl 4-({[4-bromo-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate (250 mg, 0.41 mmol) from Example 61, and 2.0 M hydrochloric saturated dioxane (0.5 mL) in ethanol (3 mL) provided the hydrochloride salt of 4- bromo-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (215 mg).
[0300] MS (ES) m/z 497.7;
HRMS: calcd for Ci9H20BrN3O4S2 + H+, 498.01513; found (ESI, [M+H]+), 498.0159;
HPLC purity 98.1% at 210-370 nm, 7.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 63. 4-Bromo-l-(phenylsulfonyl)-N-(tetrahydro-2//-pyran-4-yl)-l//-indole-3- sulfonamide
[0301] As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.23 mmol) from Example 60, Step 3, 4-aminotetrahydropyran, (23 mg, 0.23 mmol), and triethylamine (70 μL, 0.69 mmol) in dichloromethane (3.0 mL) provided 4-bromo-l- (phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide (76 mg).
[0302J MS (ESl) m/z 499;
MS (ESI) m/z 497;
ΗRMS: calcd for C19H19BrN2O5S2 + H+, 498.99915; found (ESI, [M+H]+), 498.9987;
HPLC purity 100% at 210-370 nm, 9.4 min.; 100% at 264 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3 5/ACN+MeOH) for 1 Omin, hold 4min.
Example 64. 4-Bronio-l-(phenylsulfonyl)-Λf-(2-pyridin-2-ylethyl)-lH-indoIe-3-sulfonamide
[0303] As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (100 mg, 0.23 mmol) from Example 60, Step 3, 2-(2-aminoethyl)pyridine, (28 mg, 0.23 mmol), and triethylamine (70 μL, 0.69 mmol) in dichloromethane (3.0 mL) provided 4-bromo-l- (phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide (104 mg).
[0304] MS (ESI) m/z 520;
ΗRMS: calcd for C2IHi8BrN3O4S2 + H+, 519.99948; found (ESI, PVH-H]+), 519.9989;
HPLC purity 100% at 210-370 nm, 9.3 min.; 100% at 262 nm, 9.3 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 65. 4-Bromo-l-(phenylsulfonyl)-Λ'-[2-(tetrahydro-2//-pyran-4-yl)ethyl]-l//- indole-3-sulfonamide
[0305] As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (100 mg, 0.23 mmol) from Example 60, Step 3, 4-(2-aminoethyl)tetrahydropyran, (30 mg, 0.23 mmol), and triethylamine (70 μL, 0.69 mmol) in dichloromethane (3.0 mL) provided 4- bromo-l-(phenylsulfonyl)-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-lH-indole-3-sulfonamide (63 mg).
[0306] MS (ESI) m/z 527;
MS (ESI) m/z 525;
ΗRMS: calcd for C2IH23BrN2O5S2 + H+, 527.03045; found (ESI, [M+H]+), 527.0303;
HPLC purity 100% at 210-370 nm, 9.7 min.; 100% at 264 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 66. 4-Bromo-N-(2-phenylethyl)-l-(phenylsulfonyl)-lH-indoIe-3-suIfonamide
[0307] As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (100 mg, 0.23 mmol) from Example 60, Step 3, phenethylamine, (28 mg, 0.23 mmol), and triethylamine (70 μL, 0.69 mmol) in dichloromethane (3.0 mL) provided 4-bromo-N-(2- phenylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (42 mg).
[0308] MS (ESI) m/z 519;
MS (ESI) m/z 517;
HRMS: calcd for C22Hi9BrN2O4S2 + H+, 519.00424; found (ESI, [M+H]+), 519.0027;
HPLC purity 100% at 264 nm, 10.6 min.; 100% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 67. 4-Bronio-Λr-[l-(4-cyanobenzoyl)piperidin-4-ylJ-l-(phenylsulfonyl)-lH-indole- 3-sulfonamide
[0309| As in Example 1, Step 7, 4-bromo-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (150 mg, 0.35 mmol) from Example 60, Step 3, 4-(4-aminopiperidine-l- carbonyl)benzonitrile hydrochloride, (100 mg, 0.38 mmol), and triethylamine (120 μL, 0.686mmol) in dichloromethane (8.0 mL) provided 4-bromo-N-[l-(4-cyanobenzoyl)piperidin-4- yl]-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (57 mg).
[0310] MS (ES) m/z 627.0;
ΗRMS: calcd for C27H23BrN4O5S2 + H+, 627.03660; found (ESI, [M+H]+), 627.0367;
HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 68. 4-Ethyl-l-(phenyIsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-l//-indole-3- sulfonamide
[0311] Step l. l-(l-(Phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one
[0312] As in Example 34, Step 2, 1 -(phenylsulfonyl)-l H-pyrrole (3.0 g, 15 mmol), propionyl chloride (1.3 mL, 15 mmol), and aluminum chloride (2.0 g, 15 mmol) in dichloroethane (40 mL) provided l-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one (2.9 g).
[0313] Step 2. l-(l,3-Dioxan-2-yl)-3-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)pentan-3-ol
[0314] As in Example 34, Step 3, l-(l-(phenylsulfonyl)-lH-pyrrol-3-yl)propan-l-one ( 2.9 g, 11 mmol) and (l,3-dioxan-2ylethyl)magnesium bromide (8.0 mL, 44 mmol) in
tetrahydrofuran (200 mL) provided l-(l,3-Dioxan-2-yl)-3-(l-(phenylsulfonyl)-lH-pyrrol-3- yl)pentan-3-ol (4.1 g).
[0315] Step 3. 4-Ethyl-l-(phenylsulfonyl)-lH-indole
[0316] As in Example 34, Step 4, l-(l,3-Dioxan-2-yl)-3-(l-(phenylsulfonyl)-lH- pyrrol-3-yl)pentan-3-ol (4.1 g, 11 mmol) in 6% sulfuric acid/ethanol provided 4-ethyl-l- (phenylsulfonyl)-lH-indole (1.7 g)
[0317] Step 4. 4-Ethyl-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid
[0318] As in Example 1, Step 4, 4-ethyl-l-(phenylsulfonyl)-lH-indole (200 mg, 0.7 mmol) and chlorosulfonic acid (70 μL, 1.1 mmol) in dichloromethane (7.0 mL) provided 4- ethyl-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid (256 mg, crude).
[0319] Step 5. 4-Ethyl-l-(phcnylsulfonyl)-lH-indolc-3-sulfonyl chloride
[0320] As in Example 1, Step 5, 4-ethyl-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid (260 mg, 0.7 mmol) and phosphorus pentachloride (219 g, 1.1 mmol) in phosphorus oxychloride (4.0 mL) was heated to 100 0C for five hours to give 4-ethyl-l-(phenylsulfonyl)-lH-indole-3- sulfonyl chloride (120 g).
[0321] Step 6. 4-Ethyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- sulfonamide
[0322] As in Example 1, Step 7, 4-ethyl-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (300 mg, 0.78 mmol), 4-aminotetrahydropyran hydrochloride (113 mg, 0.82 mmol), and triethylamine (160 μL, 2.0 mmol) in dichloromethane (5.0 mL) provided 4-ethyl-l- (phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide (136 mg).
[0323] MS (ES) m'z 446.9;
ΗPLC purity 93.5% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACΝ+MeOΗ) for lOmin, hold 4min.
Example 69. 4-Ethyl-l-(phenylsulfonyI)-yV-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide
[0324] As in Example 1, Step 7, 4-ethyl-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (300 mg, 0.78 mmol) from Example 68, Step 5, 2-(2-aminoethyl)pyridine (98 μg, 0.82 mmol), and pyridine (126 μL, 1.6 mmol) in dichloromethane (5.0 mL) provided 4-ethyl-l- (phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide (136 mg).
[0325] MS (ES) m/z 467.9;
HPLC purity 86.2% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 70. tert-Buty\ 4-({[4-ethyl-l-(phenylsulfonyl)-l//-indol-3- yl]sulfonyl}amino)piperidine-l-carboχylate
[0326] As in Example 1, Step 7, 4-ethyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (210 mg, 0.60 mmol) from Example 68, Step 5, 4-amino-l-Boc-piperidine (121 mg, 0.60 mmol), and triethylamine (191 μL, 1.4 mmol) in dichloromethane (6.0 mL) provided tert- butyl 4-({[4-ethyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l-carboxylate (197 mg).
[0327] MS (ES) m/z 546.1 ;
ΗPLC purity 100% at 210-370 nm, 11.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 71. 4-Ethyl-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide
[0328] As in Example 9, Step 2 ter/-butyl 4-({[4-ethyl-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate (250 mg, 0.41 mmol) from Example 70, and 2.0 M
hydrochloric saturated dioxane (2.0 mL) in ethanol (2.0 mL) provided the hydrochloride salt of 4-ethyl-l -(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (73 mg).
[0329| MS (ESI) tn/z 448;
ΗRMS: calcd for C2]H25N3O4S2 + H1, 448.13592; found (ESI, [M+H]+), 448.1331;
HPLC purity 89.0% at 210-370 nm, 8.3 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 72. 4-Ethyl-l-(phenylsulfonyI)-N-(tetrahydro-2//-pyran-4-ylinethyl)-LH-indole-3- sulfonamide
[0330] As in Example 1, Step 7, 4-ethyl-l -(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (175 mg, 0.46 mmol) from Example 68, Step 5, (tetrahydro-2H-pyran-4- yl)methanamine (53 μg, 0.46 mmol), and morpholinomethyl-polystyrene (500 mL, excess) in dichloromethane (4.0 mL) provided 4-ethyl-l -(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4- ylmethyl)-lH-indole-3-sulfonamide (98 mg).
[03311 MS (ES) m/z 461.1;
ΗRMS: calcd for C22H26N2O5S2 + H+, 463.13559; found (ESI, [M+Hf), 463.134;
HPLC purity 98.7% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 73. 4-Ethyl-l-(phenylsulfonyl)-yV-(2-pyridin-3-yIethyl)-li/-indole-3-sulfonamide
[0332] As in Example 1, Step 7, 4-ethyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (175 mg, 0.46 mmol) from Example 68, Step 5, 3-(2-aminoethyl)pyridine (56 μg, 0.46 mmol), and morpholinomethyl-polystyrene (500 niL, excess) in dichloromethane (4.0 mL) provided 4-ethyl-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide (61 mg).
[0333] MS (ESI) m/z 470;
MS (ESl) m/z 468;
ΗRMS: calcd for C23H23N3O4S2 + H+, 470.12027; found (ESI, [M+H]+), 470.1206;
HPLC purity 100% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 74. 4-MethyI-l-(phenylsulfonyl)-iV-(tetrahydro-2/-r-pyran-4-yl)-lH-indole-3- sulfonainide
[0335] As in Example 1, Step 3, 4-methylindole (500 mg, 3.8 mmol), 60% sodium hydride (213 mg, 5.3 mmol) benzenesulfonyl chloride (538 μL, 4.2 mmol) in dimethylformamide (15 mL) provided l-benzenesulfonyl-4-methyl-lH-indole (729 mg)
[0336] Step 2. l-BenzenesulfonyM-methyl-lH-indole-S-sulfonic acid
[0337] Following the procedure from Patent 2004014300, 19 Feb 2004, 1- benzenesulfonyl-4-methyl-lH-indole (700 mg, 2.6 mmol), acetic anhydride (730 mL, 7.7 mmol), and sulfuric acid (193 μL, 3.6 mmol) in dichloromethane (10 mL) provided 1-benzenesulfonyl- 4-methyl-lH-indole-3-sulfonic acid (500 mg crude).
[0338] Step 3. l-Benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride
[0339] As in Example 1, Step 5, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonic acid (500 mg, 1.4 mmol) and phosphorus pentachloride (444 mg, 2.1 mmol) in phosphorus oxychloride (7.0 mL) provided l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (221 g).
[0340] Step 4. 4-Methyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- sulfonaraide
[0341] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lΗ-indole-3-sulfonyl chloride (150 mg, 0.41 mmol), 4-aminotetrahydropyran (56 mg, 0.41 mmol), and triethylamine (113 μL, 0.81) in dichloromethane (5.0 mL) provided 4-methyl-l-(phenylsulfonyl)-N- (tetrahydro-2H-ρyran-4-yl)-lH-indole-3-sulfonamide (61 mg).
[0342] MS (ESI) m/z 435;
MS (ESI) m/z 433;
ΗPLC purity 100% at 210-370 run, 9.5 min.; 100% at 256 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 75. 4-Methyl-l-(phenylsulfonyl)-iV-(2-pyridin-2-yIethyl)-lil-r-indole-3-sulfonainide
[0343] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (150 mg, 0.41 mmol) from Example 74, Step 3, 2-(2-aminoethyl)pyridine (50 mg, 0.41 mmol), and triethylamine (113 μL, 0.81) in dichloromethane (5.0 mL) provided 4-methyl-l- (phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide (66 mg).
[03441 MS (ESI) m/z 456;
HPLC purity 100% at 210-370 nm, 9.4 min.; 100% at 258 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. BufF. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 76, 4-Methyl-l-(phenylsulfonyl)-Λ'r-(2-pyridin-4-ylethyl)-1-ιf-indθle-3-sulfonainide
[0345] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (150 mg, 0.41 mmol) from Example 74, Step 3, 4-(2-aminoethyl)pyridine (50 mg, 0.41 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (4.0 mL) provi ded 4-methyl -1 -(phenyl sulfonyl)-N-(2-py ridi n-4-y lethyl)- lH-indol e-3-sulfonami de(66 mg).
[0346] MS (ESI) m/z 456;
MS (ESI) m/z 454;
ΗPLC purity 94.2% at 210-370 nm, 8.7 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 77. 4-Methyl-l-(phenylsulfonyl)-iV-(2-pyridin-3-ylethyI)-l//-indole-3-suIfonainide
[0347] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (150 mg, 0.41 mmol) from Example 74, Step 3, 3-(2-aminoethyl)pyridine (50 mg, 0.41
mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (4.0 mL) provided 4-methyl-l-(phenyIsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide (98 mg)-
[03481 MS (ESl) m/z 456;
MS (ESI) m/z 454;
HPLC purity 95.1% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACΝ+MeOH) for lOmin, hold 4min.
Example 78. 4-Methyl-l-(phenylsulfonyl)-N-(tetrahydro-2//-pyran-4-ylmethyl)-lΛ|r-indole- 3-sιilfonaniide
[0349] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (150 mg, 0.41 mmol) from Example 74, Step 3, 4-aminomethyltetrahydropyran (47 mg, 0.41 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (4.0 mL) provided 4-methyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide (71 mg).
[0350] MS (ESI) m/z 449;
MS (ESI) m/z 447;
ΗRMS: calcd for C21Η24Ν2O5S2 + H+, 449.11994; found (ESl, [M+H]+), 449.1184;
HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 79. ^Chloro-l-CphenylsulfonylJ-N^tetrahydro-ΣH-pyran^-ylmethylJ-lH-indole- 3-sulfonamide
[0351] Step 1. l-Benzenesulfonyl-4-chloro-lH-indole
[0352] As in Example 1, Step 3, 4-chloroindole (2.0 g, 13 mmol), 60 % sodium hydride (1.3 g, 33 mmol) benzenesulfonyl chloride (4.8 mL, 20 mmol) in dimethylformamide (200 mL) provided l-benzenesulfonyl-4-chloro-lH-indole (2.2 g)
[0353] Step 2. l-Benzenesulfonyl-4-chloro-lH-indole-3-sulfonic acid
[0354] As in Example 1, Step 4, l-benzenesulfonyl-4-chloro-lH-indole (2.0 g, 6.9 mmol) and chlorosulfonic acid (0.45 mL, 6.9 mmol) in dichloromethane (70 mL) provided 1- benzenesulfonyl-4-chloro-lH-indole-3-sulfonic acid (2.5 g crude).
[0355] Step 3. l-Benzenesulfonyl-4-chloro-lH-indole-3-sulfonyl chloride
[0356] As in Example 1, Step 5, l-benzenesulfonyM-chloro-lH-indole-S-sulfonic acid (2.5 g, 6.9 mmol) and phosphorus pentachloride (2.1 g, 10 mmol) in phosphorus oxychloride (12 mL) provided l-benzenesulfonyl-4-chloro-lH-indole-3-sulfonyl chloride (2.3 g).
[0357] Step 4. 4-Chloro-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide
[0358] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lΗ-indole-3-sulfonyl chloride (200 mg, 0.51 mmol), 4-aminomethyltetrahydropyran (59 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro- l-(phenylsulfonyl)-Ν-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3-sulfonamide (41 mg).
[0359] MS (ES) m/z 467.0;
HPLC purity 100% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 80. 4-Chloro-l-(phenylsulfonyl)-N-(tetrahydro-2//-pyran-4-yl)-l//-indole-3- sulfonamide
[0360] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, 4-aminotetrahydropyran (52 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro-l -(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-1 H-indole-3-sulfonamide
(89 mg).
[0361] MS (ES) m/z 453.0;
HRMS: calcd for Ci9Hi9ClN2O5S2 + H+, 455.04967; found (ESI, [M-I-H]+), 455.046;
HPLC purity 96.4% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.
Example 81. ethyl 4-({[4-chloro-l-(phenylsuIfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate
[0362] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lΗ-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, ethyl 4-amino-l-piperidne carboxylate (88 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided ethyl 4-({[4-chloro-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate (25 mg).
[0363| MS (ES) m/z 526.0;
ΗPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 82. 4-ChIoro-l-(phenylsulfonyI)-Λr-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide
[0364] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lΗ-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, 3-(2-aminoethyl)pyridine (62 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide (72 mg).
[0365] MS (ES) m/z 476.0;
HRMS: calcd for C2IH18ClN3O4S2 + H\ 476.05000; found (ESI, [M+H]*), 476.0524; HPLC purity 100% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amraon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 83. 4-Chloro-l-(phenyIsulfonyl)-/V-(2-pyridin-2-ylethyl)-l/f-indoIe-3-sulfonamide
[0366] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, 2-(2-aminoethyl)pyridine (62 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide (34 mg).
[0367] MS (ESI) m/z 476;
ΗPLC purity 95.0% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 84. 4-Chloro-l-(phenylsult'onyl)-/V-(2-pyridin-4-ylethyl)-lH-indoIe-3-sulfonamide
[0368] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lΗ-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, 2-(2-aminoethyl)pyridine (62 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide (34 mg).
[0369] MS (ES) m/z 476.0;
ΗRMS: calcd for C2IH18ClN3O4S2 + H+, 476.05000; found (ESI, PvH-H]+), 476.05;
HPLC purity 95.5% at 210-370 nm, 8.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 85. 4-Chloro-N-(cyanomethyl)-l-(phenylsulfonyl)-l/f-indole-3-sulfonaniide
[0370] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, aminoacetonitrile hydrochloride (47 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro-N-(cyanomethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (30 mg).
[0371] MS (ES) m/z 408.0;
ΗRMS: calcd for Ci6H12ClN3O4S2 + H+, 410.00305; found (ESI, [M+H]*), 410.0027;
HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 86. N-Il-(4-tert-Butylbenzoyl)piperidin-4-yl]-4-cyano-l-(phenylsulfonyl)-lH- indole-3-sulfonamide
[0373] As in Example 1, Step 3, lH-indole-4-carbonitrile (5.0 g, 35 mmol), 60 % sodium hydride (3.5 g, 88 mmol) benzenesulfonyl chloride (6.8 mL, 53 mmol) in dimethylformamide (200 mL) provided l-(phenylsulfonyl)-lH-indole-4-carbonitrile (6.5 g).
[0374J Step 2. 4-Cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid
[0375] As in Example 1, Step 4, l-(phenylsulfonyl)-lH-indole-4-carbonitrile (8.0 g, 28 mmol) and chlorosulfonic acid (1.9 mL, 28 mmol) in dichlorom ethane (250 mL) provided 4- cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid (10 g crude).
[0376] Step 3. 4-Cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride
[0377] As in Example 1 Step 5, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid (10 g, 28 mmol) and phosphorus pentachloride (8.9 g, 42 mmol) in phosphorus oxychloride (60 mL) provided l-benzenesulfonyl-4-chloro-lH-indole-3-sulfonyl chloride (2.3 g).
[0378] Step 4. N-[l-(4-tert-butylbenzoyl)piperidin-4-yl]-4-cyano-l-(phenylsulfonyl)-lH- indole-3-sulfonamide
[0379] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol), (4-aminopiperidin-l-yl)(4-tert-butylphenyl)methanone (57 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided N-[l-(4-tert-butylbenzoyl)piperidin-4-yl]-4-cyano- 1 -(phenylsulfonyl)- lH-indole-3- sulfonamide (48 mg).
[0380] MS (ES) m/z 605.2;
HRMS: calcd for C31H32N4O5S2 + H+, 605.18869; found (ESI, [M+Hf), 605.1917;
HPLC purity 97.5% at 210-370 nm, 10.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 87. 4<tyano-l-(phenylsulfonyl)-Λ^tetrahydro-2H-pyran-4-yl)-l//-indole-3- sulfonamide
[0381] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 4-aminotetrahydrofϋran hydrochloride (30 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- sulfonamide (65 mg).
[0382] MS (ES) m/z 444.0;
HRMS: calcd for C20Hi9N3O5S2 + H*. 446.08389; found (ESI, [M+H]1), 446.0835; HPLC purity 98.4% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 88. /erf- Butyl 4-({[4-cyano-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate
[0383] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, l-Boc-4-aminopiperidine (44 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided fe/7-butyl 4-({ [4-cyano- 1 -(phenylsulfonyl)- lH-indol-3-yl]sulfonyl }amino)piperidine- 1 - carboxylate (47 mg).
[0384] MS (ES) m/z 543.1 ;
ΗPLC purity 91.6% at 210-370 nm, 10.2 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 89. 4-Cyaιio-l-(phenyIsulfonyl)-iV-piperidin-4-yl-lH-indole-3-sulfonamide
[0385] As in Example 9, Step 2 /erf-Butyl 4-({[4-cyano-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l -carboxylate (70 mg, 0.13 mmol) from Example 88, and 2.0 M
hydrochloric saturated dioxane (2.0 mL) in ethanol (2.0 mL) provided the hydrochloride salt of 4-cyano-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide (45 mg).
[0386] MS (ES) m/z 445.1 ;
ΗRMS: calcd for C20H20N4O4S2 + H+, 445.09987; found (ESI, [M+H]+), 445.0999;
HPLC purity 98.1% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 90. 4-Cyano-l-(phenylsulfonyl)-N-(2-pyridin-2-yIethyI)-lH-indole-3-sulfonamide
[0387] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 2-(2-aminoethyl)pyridine (27 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide (39 mg).
[0388] MS (ES) m/z 467.1 ;
ΗRMS: calcd for C22H18N4O4S2 + H+, 467.08422; found (ESI, [M+H]+), 467.0833;
HPLC purity 99.2% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 91. 4-Cyano-N-(2-methoxyethyI)-l-(phenyIsulfonyl)-lH-indole-3-sulfonamide
[0389] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lΗ-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 2-methoxyethylamine (17 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL)
provided 4-cyano-N-(2-methoxyethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (56 mg).
[0390] MS (ES) m/z 420.1;
ΗRMS: calcd for Ci8H17N3O5S2 + H+, 420.06824; found (ESI, [M+H]+), 420.07;
HPLC purity 99.5% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 92. 4-Cyano-Λ'-(2-morpholin-4-ylethyl)-l-(phenylsulfonyl)-l//-indole-3- sulfonamide
[0391] As in Example 1, Step 7, 4-cyaπo-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 2-methoxy ethyl amine (29 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-N-(2-morpholin-4-ylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide (64 mg).
[0392] MS (ES) m/z 475.1 ;
ΗRMS: calcd for C2IH22N4O5S2 + H+, 475.11044; found (ESl, [M+H]'), 475.1106;
HPLC purity 98.6% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 93. 4-Cyano-l-(phenylsulfonyl)-iV-(2-pyridin-3-ylcthyl)-l//-indole-3-sulfonamidc
[0393] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 3-(2-aminoethyl)pyridine (27 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide (28 mg).
[0394] MS (ES) m/z 461.1 ;
ΗRMS: calcd for C22H18N4O4S2 + H+, 467.08422; found (ESI, [M+H]*), 467.0845;
HPLC purity 98.6% at 210-370 nm, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 94. 4-Cyano-l-(phenylsulfonyI)-iV-(2-pyridin-4-ylethyI)-li/-indoIe-3-sulfonamide
[0395] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, 4-(2-aminoethyl)pyridine (27 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-l-(phcnylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indolc-3-sulfonamidc (29 mg).
[0396] MS (ES) m/z 467.1;
ΗRMS: calcd for C22Hi8N4O4S2 + H+, 467.08422; found (ESI, [M+H]+), 467.0745;
HPLC purity 99.0% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 95. 4-Cyano-l-(phenylsuIfonyl)-iV-(2-piperidin-l-ylethyl)-l/f-indole-3- sulfonamide
[0397] As in Example 1, Step 7, 4-cyano-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (70 mg, 0.18 mmol) from Example 86, Step 3, l-(2-aminoethyl)piperidine (28 mg, 0.22 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (10 mL) provided 4-cyano-l-(phenylsulfonyl)-N-(2-piperidin-l-ylethyl)-lH-indole-3-sulfonaniide (54 mg).
[03981 MS (ES) m/z 473.1 ;
ΗRMS: calcd for C22H24N4O4S2 + H+, 473.131 17; found (ESI, [M+H]+), 473.127;
HPLC purity 100% at 210-370 nm, 7.4 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 96. 4-Chloro-l-(phenyIsuIfonyl)-/V-(2-piperidin-l-yIethyl)-li/-indole-3- sulfonamide
[0399] As in Example 1, Step 7, l-benzenesulfonyl-4-methyl-lH-indole-3-sulfonyl chloride (200 mg, 0.51 mmol) from Example 79, Step 3, l-(2-aminoethyl)piperidine (66 mg, 0.51 mmol), and morpholinomethyl polystyrene (500 mg, excess) in dichloromethane (7.0 mL) provided 4-chloro-l-(phenylsulfonyl)-N-(2-piperidin-l-ylethyl)-lH-indole-3-sulfonamide (33 mg).
[0400] MS (ES) m/z 482.1;
HRMS: calcd for C2IH24ClN3O4S2 + Hf, 482.09695; found (ESI, [M+H]4), 482.1007; HPLC purity 100% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 ram column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Exam pie 97. 4-[2-({ [4-(M ethoxycar bonyl)-l -(phenylsulfonyl)- 1 H-indθl-3- yl|sulfonyl}amino)ethyl]benzoic acid
[0401] Step l . Methyl l-(phenylsulfonyl)-lΗ-indole-4-carboxylate
[0402] As in Example 1, Step 3, methyl lH-indole-4-carboxylate (5.0 g, 29 mmol), 60 % sodium hydride (2.9 g, 71 mmol) benzenesulfonyl chloride (4.0 mL, 31 mmol) in dimethylformamide (60 mL) provided Methyl l-(phenylsulfonyl)-lH-indole-4-carboxylate (8.4 g)-
[0403] Step 2. 4-(Methoxycarbonyl)-l -(phenylsulfonyl)- lH-indole-3-sulfonic acid
[0404] As in Example 1, Step 4, l-(phenylsulfonyl)-lH-indole-4-carbonitrile (6.4 g, 20 mmol) and chlorosulfonic acid (1.5 mL, 22 mmol) in dichloromethane (35 mL) provided 4- (methoxycarbonyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonic acid (10 g crude).
[0405] Step 3. Methyl 3-(chlorosulfonyl)-l-(phenylsulfonyl)-lH-indole-4-carboxylate
[0406] As in Example 1 , Step 5, 4-cyano-l -(phenyl sulfonyl)-l H-indole-3-suifonic acid (8.0 g, 20 mmol) and phosphorus pentachloride (5.7 g, 27 mmol) in phosphorus oxychloride (150 mL) provided methyl 3-(chlorosulfonyl)-l-(phenylsulfonyl)-lH-indole-4-carboxylate (4.1 g).
[0407] Step 4. 4-[2-({[4-(Methoxycarbonyl)-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl }amino)ethyl]benzoic acid
[0408] As in Example 1, Step 7, methyl 3-(chlorosulfonyl)-l-(phenylsulfonyl)-lΗ- indole-4-carboxylate (400 mg, 0.97 mmol), 4-(2-aminoethyl)benzoic acid (180 mg, 1.1 mmol), and diisopropylethylamine (420 mg, 2.4 mmol) in dichloromethane (10 mL) provided 4-[2-({[4- (methoxycarbonyl)-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl }amino)ethyl]benzoic acid (59 mg)-
[0409] MS (ES) m/z 543.0;
ΗRMS: calcd for C25H22N2O8S2 + H+, 543.08903; found (ESI, [M+H]+), 543.0881;
HPLC purity 100% at 210-370 nm, 9.7 min.; XterraRPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 98. Methyl l-(phenylsulfonyl)-3-{f(2-pyridin-3-ylethyl)amino]sulfonyl}-lH- indole-4-carboxylate
[0410] As in Example 1, Step 7, methyl 3-(chlorosulfonyl)-l-(phenylsulfonyl)-lΗ- indole-4-carboxylate (400 mg, 0.97 mmol) from Example 97, Step 3, 3-(2-aminoethyl)pyridine (130 mg, 1.1 mmol), and diisopropylethylamine (420 mg, 2.4 mmol) in dichloromethane (10 mL) provided methyl l-(phenylsulfonyl)-3-{[(2-pyridin-3-ylethyl)amino]sulfonyl}-lH-indole-4- carboxylate (61 mg).
10411] MS (ES) m/z 500.0;
ΗRMS: calcd for C23H21N3O6S2 + H+, 500.09445; found (ESI, [M+HJ+), 500.0921;
HPLC purity 100% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 99. Methyl l-(phenylsulfonyl)-3-{f(2-pyridin-4-ylethyl)amino]suIfonyl}-lH- indole-4-carboxylate
[0412] As in Example 1, Step 7, methyl 3-(chlorosulfonyl)-l-(phenylsulfonyl)-lH- indole-4-carboxylate (400 mg, 0.97 mmol) from Example 97, Step 3, 4-(2-aminoethyl)pyridine (130 mg, 1.1 mmol), and diisopropylethylamine (420 mg, 2.4 mmol) in dichloromethane (10 mL) provided methyl l-(phenylsulfonyl)-3-{[(2-pyridin-4-ylethyl)amino]sulfonyl}-lH-indole-4- carboxylate (62 mg).
[0413] MS (ES) m/z 500.0;
ΗRMS: calcd for C23H21N3O6S2 + H+, 500.09445; found (ESI, [M+H]+), 500.0892;
HPLC purity 100% at 210-370 nm, 8.6 min.; XterraRPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 100. Methyl 3-{[(f/-fl/is-4-hydroxycyclohexyl)amino]sulfonyl}-l-(phenylsuIfonyl)- lH-indole-4-carboxyIate H
[0414] As in Example 1, Step 7, methyl 3-(chlorosulfonyl)-l-(phenylsulfonyl)-lH- indole-4-carboxylate (400 mg, 0.97 mmol) from Example 97, Step 3, trans-4-aminocyclohexanol (120 mg, 1.1 mmol), and diisopropylethylamine (420 mg, 2.4 mmol) in dichloromethane (10 mL) provided methyl 3-{[(<rα/?5-4-hydroxycyclohexyl)amino]sulfonyl}-l-(phenylsulfonyl)-lH- indole-4-carboxylate (49 mg).
[0415] MS (ES) m/z 493.0;
ΗRMS: calcd for C22H24N2O7S2 + H+, 493.10977; found (EST, [M+H]4), 493.1095;
HPLC purity 97.9% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 101. 4-Isopropyl-l-(phenylsulfonyl)-Λ^2,2,6,6-tetramethylpiperidin-4-yl)-lH- indole-3-sulfonamide
[0416] As in Example 1, Step 7, 4-isopropyl-l-(phenylsulfonyl)-lH-indole-3-sulfonyl chloride (212 mg, 0.53 mmol) from Example 34, Step 6, 4-amino-2,2,6,6-tetramethylpiperidine (100 mg, 0.64 mmol), and triethylamine (190 μL, 1.3 mmol) in dichloromethane (50 mL) provided 4-isopropyl-l-(phenylsulfonyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-lH-indole-3- sulfonamide (650 mg).
[0417] MS (ES) m/z 517.9;
ΗRMS: calcd for C26H35N3O4S2 + H+, 518.21417; found (ESI, [M+Iff), 518.2137;
HPLC purity 100% at 210-370 nm, 9.2 min.; XterraRPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 102. tørt-Butyl 4-({[7-(phenylsιιlfonyl)-4-(trifluoromethyl)-lH-indoI-3- yl]sulfonyl}amino)piperidine-l-carboxylate
[0418] A mixture of 4-chloro-3-nitrobenzotrifluoride (2.0 mL, 14 mmol) and benzenesulfinic acid (2.3 g, 14 mmol) in DMSO was warmed to ~50 0C for 2 h. The resulting orange solution was diluted with water and extracted with ethyl acetate. The organic extracts were dried (MgSO4), filtered, and concentrated to afford crude l-benzenesulfonyl-2-nitro-4- trifluoromethylbenzene. The crude l-benzenesulfonyl-2-nitro-4-trifluoromethylbenzene was dissolved in THF (140 mL) and cooled to -40 0C. Vinylmagnesium bromide (55 mL, 55 mmol, 1 M in THF) was added to the cooled solution and the resulting solution was stirred for 30 min at -40 0C and then quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted with ethyl acetate, dried (MgSO4), filtered, and concentrated. The crude material was purified by flash column chromatography through silica gel (gradient elution with 0-25% ethyl acetate-hexane) to afford 7-benzenesulfonyl-4-trifluoromethyl-lH-indole. A solution of 7- benzenesulfonyl-4-trifluoromethyl-lH-indole (2.0 g, 6.1 mmol) in dichloromethane (20 mL) was treated dropwise with chlorosulfonic acid (2 mL, 30 mmol) and the resulting solution was maintained at ambient temperature for 1 h. The solution was then filtered through silica gel to afford 7-benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl chloride. A solution of 7- benzenesulfonyl-4-trifluoromethyl-lH-indole-3-sulfonyl chloride (1.5 g, 3.5 mmol) in dichloromethane (20 mL) was treated sequentially with diisopropylethylamine (1.2 mL, 6.9 mmol) and 4-amino-N-Boc-piperidine (0.78 g, 3.9 mmol). The reaction mixture was stirred overnight at room temperature and then quenched with water and diluted with ethyl acetate. The phases were separated and the organic phase was washed with saturated aqueous ammonium chloride, sodium bicarbonate, and brine. The organic phase was dried (MgSO4), filtered, and concentrated to provide /e/7-butyl 4-({[7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate which was purified by flash column chromatography through silica gel (gradient elution with 0-25% ethyl acetate-hexane).
[0419] MS (ESI) m/z 586.1;
HPLC purity 97.5% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Aramon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.
Example 103. 7-(PhenyIsulfonyl)-7V-piperidin-4-yl-4-(trifluoromethyl)-lH-indoIe-3- sulfonamide
[0420] A solution of tar/-butyl 4-({[7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate (0.33 g, 0.56 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (2 mL). After 30 min, the reaction mixture was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and filtered. The ethyl acetate solution was treated with 1 N HCl in dioxane (1 mL) and the resulting cloudy solution was allowed to stand at ambient temperature overnight. The product was then isolated by filtration and the solid was dried in the vacuum oven to provide 7- (phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH-indole-3-sulfonamide, as its hydrochloride salt.
[0421] MS (ES) m/z 487.8;
ΗPLC purity 97.7% at 210-370 nm, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 104. T-CPhenylsuIfonylJ-N-Il-CtrifluoroacetyOpiperidin-^yll-^trifluoromethyl)- lH-indole-3-sulfonamide
[0422] A solution of 7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH- indole-3-sulfonamide, hydrochloride salt (0.10 g, 0.19 mmol) in dichloromethane (5 mL) was treated sequentially with trifluoroacetic anhydride (29 μL, 0.21 mmol) and diisopropylethylamine (73 μL, 0.42 mmol). The reaction mixture was stirred overnight at ambient temperature and then concentrated. The crude product was purified by flash column chromatography through silica gel (gradient elution with 0-30% ethyl acetate-hexane) to afford T^phenylsulfony^-N-fl-^rifluoroacetyOpiperidin^-ylJ^-^rifluoromethy^-lH-indole-S- sulfonamide.
[0423] MS (ES) m/z 583.8;
ΗPLC purity 98.7% at 210-370 nm, 9.7 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 105. N-[l-(2,2-Dimethylpropanoyl)piperidin-4-yI]-7-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide
[0424] As in Example 104, 7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)- lH-indole-3-sulfonamide, hydrochloride salt (0.10 g, 0.19 mmol), 2,2-dimethylpropionyl chloride (26 μL, 0.21 mmol) and diisopropylethylamine (73 μL, 0.42 mmol) in dichloromethane (5 mL) provided N-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]-7-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indole-3-sulfonamide.
[04251 MS (ES) m/z 571.8;
ΗPLC purity 99.1% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACΝ+MeOΗ) for lOmin, hold 4min.
Example 106. N-{l-[(DimethyIamino)sulfonylJpiperidin-4-yl}-7-(phenylsuIfonyl)-4- (trifluoromethyl)-lH-indole-3-suIfonamide
[0426] As in Example 104, 7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)- lH-indole-3-sulfonamide, hydrochloride salt (0.10 g, 0.19 mmol), dimethylsulfamoyl chloride (23 μL, 0.21 mmol) and diisopropylethylamine (73 μL, 0.42 mmol) in dichloromethane (5 mL) provided N-(I -[(dimethylamino)sulfonyl]piperidin-4-yl}-7-(phenylsulfonyl)-4-(trifluoromethyl)- lH-indole-3-sulfonamide.
10427] MS (ES) m/z 594.8;
ΗPLC purity 95.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACΝ+MeOΗ) for lOmin, hold 4min.
Example 107. 3-{[4-({[7-(PhenylsuIfonyl)-4-(trifluoromethyl)-li/-indol-3- yl]sulfonyl}amino)piperidin-l-yl]sulfonyl}benzoic acid
[0428] As in Example 104, 7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)- lH-indole-3-sulfonamide, hydrochloride salt (0.10 g, 0.19 mmol), 3-(chlorosulfonyl)benzoic acid (46 mg, 0.21 mmol) and diisopropylethylamine (73 μL, 0.42 mmol) in dichloromethane (5 mL) provided 3-{ [4-({ [7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]sulfonyl}benzoic acid.
[04291 MS (ES) m/z 671.8;
ΗPLC purity 96.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACΝ+MeOΗ) for lOmin, hold 4min.
Example 108. 7-(Phenylsulfonyl)-4-(trifluoromethyl)-yV-{l- [(trifluoromethyI)sulfonyl]piperidin-4-yl}-lH-indole-3-sulfonamide
[0430] As in Example 104, 7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)- lH-indoIe-3-sulfonamide, hydrochloride salt (0.10 g, 0.19 mmol), trifluoromethanesulfonic anhydride (35 μL, 0.21 mmol) and diisopropylethylamine (73 μL, 0.42 mmol) in
dichloromethane (5 mL) provided 7-(phenylsulfonyl)-4-(trifluoromethyl)-N-{ l- [(trifluoromethyl)sulfonyl]piperidin-4-yl}-lH-indole-3-sulfonamide.
[0431] MS (ES) m/z 619.7;
ΗPLC purity 85.6% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 109. tert-Butyl 4-({[l-raethyl-7-(phenylsulfonyl)-4-(trifluoromethyI)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate
[0432] A solution of 7-benzenesulfonyl-4-trifluoromethyl-lH-indole (1.0 g, 3.1 mmol) in dimethylformamide (10 mL) was treated with 60% sodium hydride (0.18 g, 4.5 mmol). The mixture was stirred at room temperature for 30 min and then iodomethane (0.29 mL, 4.7 mmol) was introduced. The resulting mixture was stirred for 4 h at ambient temperature and then quenched with water and diluted with ethyl acetate. The phases were separated and the organic phase was washed with saturated aqueous ammonium chloride, sodium bicarbonate, and brine. The organic phase was dried (MgSO4), filtered, and concentrated to afford 7-benzenesulfonyl-l- rnethyl-4-trifluoromethyl-lΗ-indole. As in Example 1, 7-benzenesulfonyl-l -methyl -4- trifluoromethyl-lH-indole (0.70 g, 2.1 mmol) and chlorosulfonic acid (0.5 mL, 7.5 mmol) in dichloromethane (20 mL) provided 7-benzenesulfonyl-l-rnethyl-4-trifluoromethyl-lH-indole-3-
sulfonyl chloride. As in Example 1, 7-benzenesulf6nyl-l-rnethyl-4-trifluoromethyl-lH-indole-3- sulfonyl chloride (0.90 g, 2.1 mmol), diisopropylethylamine (0.54 mL, 3.1 mmol), and 4-amino- N-Boc-piperidine (0.50 g, 2.5 mmol) in dichloromethane (20 mL) provided tert-butyl 4-({[l- methyl-7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate.
[0433] MS (ES) m/z 600.0;
ΗPLC purity 100.0% at 210-370 nm, 13.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 110. l-Methyl-7-(phenylsuIfonyI)-Λr-piperidin-4-yl-4-(trifluoromethyl)-Uϊ-indole- 3-suIfonamide
[0434J As in Example 103, treatment of /er/-butyl 4-({ [ 1 -methyl-7-(phenylsulfonyl)-4- (trifluoromethyl)-lH-indol-3-yl]sulfonyl }amino)piperidine- 1 -carboxylate with trifluoroacetic acid in dichloromethane provided l-methyl-7-(phenylsulfonyl)-iV-piperidin-4-yl-4- (trifluoromethyl)-lH-indole-3-sulfonamide, as its hydrochloride salt.
[0435) MS (ES) m/z 502.1;
ΗPLC purity 100.0% at 210-370 nm, 7.4 min.; Xterra RPlδ, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOΗ) for lOmin, hold 4min.
Example 111: Fluorescence Polarization Binding Assay
[0436] The affinity of test compounds for SFRP-I was determined using a fluorescence polarization binding assay. According to the assay design, a probe compound was bound to
SFRP-I . The fluorescence anisotropy value of the probe compound is increased upon binding to SFRP-I . Upon the addition of a test compound, the fluorescence anisotropy value for the probe compound decreased due to competitive displacement of the probe by the test compound. The decrease in anisotropy as a function of increasing concentration of the test compound provides a direct measure of the test compound's binding affinity for SFRP-I.
[0437] To determine IC50 values, fluorescence polarization experiments were conducted in a 384-well format according to the following procedures. A 20 mM stock solution of the probe compound was prepared in 100 % DMSO and dispensed in 10 μL aliquots for long- term storage at -200C. The binding assay buffer was prepared by combining stock solutions of Tris-Cl, NacL, glycerol, and NP40 at final concentrations of 25 mM Tris-Cl pH 7.4, 0.5 M NaCl, 5% glycerol and 0.002 % NP40. Master stock solutions of the test compounds were prepared in 100 % DMSO at final concentrations of 20 mM. Typically the working stock solutions of the test compounds were prepared by serially diluting the 20 mM master stock solution to 5 mM, 2.5 mM, 1.25 mM, 0.625 mM, 0.3125 mM, 0.156 mM, 78 μM, 39 μM, 19.5 μM, 9.8 μM, 4.9 μM, 2.44 μM, 1.22 μM, 0.31 μM, 76 nM, and 19 nM in DMSO. The working stock solutions of the test compounds were further diluted by combining 6 μl of the solutions with 24 μL of Milli-Q purity water, resulting in working stock solutions (10x compound stocks) in 20 % DMSO.
[0438] The assay controls were prepared as follows. A 2 μL aliquot of the 20 mM fluorescence probe compound was diluted 1000-fold in 100 % DMSO to a final concentration of 20 μM. 6 μL of the 20 μM probe was combined with 5.4 mL of the assay buffer, mixed well, and 18 μL of the resulting solution was dispensed into 384-well plates.
[0439] SFRP-1/probe complex was prepared by combining 11 μL of 20 μM probe compound with 9.9 mL of the assay buffer and SFRP-I stock solution to final concentrations of 22 nM probe compound and 50 nM SFRP-I. 18 μL of the SFRP-1/probe complex was dispensed into the 384-well plates.
[0440] 2 μL aliquots of the test compounds from the 10x working stock solutions were removed and dispensed into the plate containing the SFRP-1/probe complex and the resultant solutions were mixed by pipetting up and down once. The final concentratons of SFRP-I and probe in the assay solutions were 45 nM and 20 nM, respectively. In a typical experiment, each plate was used to test 14 compounds.
[0441] The plate was incubated in the dark for 15 minutes. The fluorescence of the SFRP-1/probe complexs was read in the Tecan Ultra plate reader at excitation and emission maxima of 485 and 535 nm. The plate reader settings were as follows:
Mode: Fluorescence Polarization Plate definition: Matrical3841v.pdf (pdf stands for Plate Definition File) Excitation 485nm (bandwidth 20nm) Emission 535nm (bandwidth 30nm) G-factor: 1.03 # flashes / well: 10 integration time: lOOus time btwn move, flash: 60ms Z-position: 10730 urn
Analysis of Results
[0442] Fluorescence anisotropy results from the emission of polarized light in the parallel and perpendicular directions when a fluorophore is excited with vertically polarized light. The anisotropy of the probe in the free and bound state was determined using the following equation: r = /(//)- /(±)÷ /(//) + 2/(l) where I(II) and 1(1) are the parallel and perpendicular emission intensities, respectively.
10443] Monitoring the anisotropy changes of the probe compound revealed that it bound saturably to SFRP-I with a KD of 20-30 nM. The binding affinity was independently verified using a tryptophan fluorescence quenching assay.
[0444] The decrease in the anisotropy of the probe upon addition of the competing test compound was fitted to a sigmoidal dose response curve of the equation shown below:
Y = Bottom + (T°!> -ff™h fflllslope
where "X" is the logarithm of concentration, "Y" is the anisotropy, and "Bottom" and "Top" correspond to the anisotropy values of the free and SFRP-1-bound probe prior to the addition of the test compound, respectively.
[0445] For automated IC50 determinations, the equation shown above was used in the program GraphPad Prism The "Flillslope" was kept constant at 1. The value for "Bottom" was fixed, but was determined by the blank (probe-only) wells in the plate. The values for "Top" and "IC50" were determined by the data fit. The value for "Top" was typically close to 120, equivalent to approximately 50 % bound probe, and the value for "Bottom" was around 30, due to free probe. If the test compound interfered with the probe in the fluorescence assay at high concentrations, the range for the fitted data was limited to the lower concentration range.
[0446] The data obtained from the experiments are shown in the table following example 103.
Example 112: Cell-based Assay for in vitro Measurement of SFRP-1/SARP2 Antagonist Activity
[0447] The following cell-based assay can be used to identify inhibitors of SFRP-I . Materials and Methods
Cells
[0448] The osteosarcoma cell line, U2OS (ATCC, HTB 96), was passaged twice a week with growth medium (McCoy's 5A medium containing 10% (v/v) fetal calf serum, 2mM GlutaMAX-1, and 1% (v/v) Penicillin- Streptomycin). The cells were maintained in vented flasks at 370C inside a 5% CCV95% humidified air incubator. One day prior to transfection, the cells were plated with growth medium at 25,000 cells/well into 96-well plates and incubated at 37 0C overnight.
Routine Co-Transfec1ion
|0449] The growth medium was removed, and the cells were washed once with OPTIMEM I (Gibco-BRL) medium (100 μL/well) to remove the serum and antibiotics. The wash medium was removed, and the cells were re-fed with OPTI-MEM I medium (100 μL/well). For each well of cells to be transfected, the following DNA's were diluted together in 25 μL OPTI-MEM I medium: 0.1 μg 16x TCF-tk-Luciferase reporter, 0.02 μg Wnt 3, Wnt3A, Wnt 1 or empty vector (Upstate Biotechnology), 0.075 μg hSFRP-1 or empty vector (pcDNA3.1, Invitrogen), and 0.025 μg CMV-βgal (Clonetech). For each well of cells to be transfected, lμl of Lipofectamine 2000 reagent (Invitrogen) was diluted in 25 μl OPTI-MEM I medium and incubated at room temperature for 5 minutes. The diluted DNA's were then combined with the diluted Lipofectamine 2000 (LF2000), and the mixture was incubated at room temperature for 20 minutes. Fifty μL of the DNA-LF 2000 mixture was added to each well, and the plate(s) were incubated at 37 0C in a 5% Cθ2/95% humidified air incubator for 4 hours. The cells were washed once with 150 μL/well of experimental medium (phenol red-free RPMI Medium 1640 containing 2% fetal bovine serum, 2mM GlutaMAX-1, and 1% Penicillin-Streptomycin). Finally, the cells were treated overnight at 37 0C with 200 μL/well of experimental medium containing either vehicle (typically DMSO) or diluted compound in replicates of 8 wells/compound.
Dosing
[0450J Initial single dose screening of test compounds was done at 10 μM .
[0451] Dose-response experiments were initially performed with the compounds in log increases of concentration from 1-10,000 nM. From these dose-response curves, ECso values were generated.
Assay
[0452] After treatment, the cells were washed twice with 150 μLΛvell of PBS without calcium or magnesium and were lysed with 50 μL/well of IX cell culture lysis reagent (Promega Corporation) on a shaker at room temperature for 30 minutes. Thirty μL aliquots of the cell lysates were transferred to 96-well luminometer plates, and luciferase activity was measured in a MicroLumat PLUS luminometer (EG&GBerthold), or a Victor (PerkinElmer Life Sciences) using 100 μL/well of luciferase substrate (Promega Corporation). Following the injection of substrate, luciferase activity was measured for 10 seconds after a 1.6 second delay. Similarly, 10 μL aliquots of the cell lysates were transferred to separate 96-well luminometer plates, and 50 μL of Galacton chemiluminescent substrate (Tropix) was added to each well. The plates were covered and incubated on a rotary shaker at room temperature for one hour, βgal activity was measured in a MicroLumat PLUS luminometer or Victor using 100 μL/well of Light Emission Accelerator (Tropix). Following the injection of the accelerator, βgal activity was measured for 10 seconds after a 1.6 second delay. The luciferase and βgal activity data were transferred from the luminometer to a PC and analyzed using the SAS/Excel program. After the luciferase activity was normalized to βgal, the SAS/Excel program was used to determine the mean and standard deviation of each treatment, to analyze the data for statistical significance, and to determine EC50 values (see the Table below).
Large-Scale Co-Transfection
[0453] As an alternative to co-transfection in a 96 well plate, the U2OS cells were transfected in T225 flasks and the transfected cells were frozen. The frozen cells were thawed and plated on a 96 well plate and the assay was carried out as detailed above. The growth medium was removed from the T225 flasks, and the cells were washed once with OPTI-MEM I medium (approx. 25 ml/flask) to remove the serum and antibiotics. The wash medium was removed, and llie cells were re-fed with OPTI-MEM I medium (59 ml/flask). For each T225 flask of cells to be transfected, the following DNA's were diluted together in 5.9 ml OPTI-MEM I medium: 70.3 μg 16x TCF-tk-Luciferase reporter, 14.06 μg WNT3, 3 A or Wntl or empty vector, 52.8 μg hSFRP-1 or empty vector, and 17.58 μg CMV-βgal. Separately, for each flask of cells to be transfected, 354 μL of Lipofectamine 2000 reagent (Invitrogen) was diluted in 5.9 mL OPTI-MEM I medium and incubated at room temperature for 5 minutes. The diluted DNA's were then combined with the diluted Lipofectamine 2000 (LF2000), and the mixture was incubated at room temperature for 20 minutes. 11.8 mL of the DNA-LF 2000 mixture was added
to each flask, and the flask(s) were incubated at 37 0C in a 5% CCh /95% humidified air incubator for 4 hours. The medium was removed, and the cells were washed once with approximately 25 mL/flask of phenol red-free RPMI Medium 1640, then re-fed with 50 mL/flask of experimental medium (phenol red-free RPMI Medium 1640 containing 2% fetal bovine serum, 2 mM GlutaMAX-1, and 1% Penicillin- Streptomycin) and incubated at 370C overnight.
Freezing Cells
[0454] The transfected cells were washed twice with 25 mL/flask/wash of PBS without calcium or magnesium. Three ml of Trypsin-EDTA (0.05% Trypsin, 0.53 mM EDTA-4Na) was added to each flask, and the flasks were incubated at room temperature for approximately 5 minutes until the cells were rounded and detached from the surface of the flask(s). The cells were resuspended in 10 mL/flask of phenol red-free RPMI 1640 containing 10% fetal bovine serum and were pipetted up and down several times until a single cell suspension was formed. The resuspended cells were pooled and a 10 μL aliquot was removed and diluted at 1.10 in PBS. The diluted cells were counted using a hemacytometer to determine the total number of cells in the pool. The cells were transferred to sterile centrifuge tubes and pelletted at 1500 rpm in a Sorvall RC-3B refrigerated centrifuge at 4 0C for 5 minutes. The supernatant was aspirated and the cells were resuspended in cold, phenol red-free RPMI 1640 medium containing 50% FBS to a cell density of 2.5E+7 cells/ml. An equal volume of cold, 2x freezing medium (phenol red-free RPMI 1640 medium containing 50% FBS and 15% DMSO) was added slowly, dropwise to the resuspended cells with gentle mixing, resulting in a final cell density of 1.25E+7 cells/mL. The resuspended cells were placed on ice and aliquoted into sterile cryogenic vials. The vials were transferred to a Nalgene Cryo 1°C freezing container (Nalgene catalog # 5100-0001) containing 250 niL isopropyl alcohol. The sealed container was placed in a -80 0C freezer overnight to freeze the cells at a cooling rate of -1 °C/minute. The frozen cells were then transferred to a - 1500C freezer for long-term storage.
Benchtop Assay for Single Dose Confirmation of HTS Hits
[0455] Early in the morning, a vial of frozen transfected cells was thawed, and the cells were resuspended in phenol red-free RPMT 1640 medium to a final cell density of 150,000 cells/ml. The resuspended cells were then plated in white, 96-well polystyrene tissue culture treated CulturPlatesTM (Packard cat. # 6005180) at a volume of 100 μL of cell suspension/well {i.e. 15,000 cells/well). The plates were incubated at 37 0C inside a 5% CC>2/95% humidified air incubator for 6 hours or until the cells were attached and started to spread. Test compounds were
then added to the wells (1 well/compound) and the plates were incubated at 37 0C overnight. After the overnight incubation, luciferase activity was measured using the Luc-Screen Luciferase Assay System (Tropix). Fifty μL of Luc-Screen buffer 1, warmed to room temperature, was added directly to the cells in the 96-well plates. Fifty μL of Luc-Screen buffer 2, warmed to room temperature, was then added, and the plates were incubated in the dark, at room temperature, for 10 minutes. The plates were transferred to a Packard Top Count Microplate Scintillation and Luminescence Counter (Packard), arid the light emission was measured for 10 seconds after a 2 minute delay.
[0456] The luciferase activity data was transferred to a PC and analyzed using the SAS/Excel program as described above. Analysis of Results
[0457] The luciferase data was analyzed using the SAS/Exccl program. For the initial single dose experiment, if the compound treatment resulted in increased reporter activity and was specific to SFRP-I inhibition, then the results were reported as fold induction over SFRP-I control. Compounds
[0458] A known inhibitor of GSK-3β, a key enzyme involved in the Wnt signaling pathway, served as an internal control for measurement of the cellular response to Wnt signaling. The inhibition of GSK-3 results in stabilization of β-catenin, leading to up-regulation of LEF/TCF regulated reporter genes.
Example ICso Inhibition Cone. EC50
(μM) (%) (μg/mL) (μM)
102 0.1 1 0.74 103 0.04 0.41 104 0.09 1.5 105 0.13 0.67 106 0.07 0.27 107 0.02 0.024 108 0.26 1.4 109 15 1.9 110 1.1 5.9
[0459] The entire disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference.
Claims
1. A compound of formul a (I) :
#
or a pharmaceutically acceptable salt thereof, wherein:
R1 is alkyl, perfluoroalkyl, halo, cyano, or CO2alkyl;
R2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl; and
R3 is optionally substituted aryl.
2. A compound of claim 1, wherein R1 is C1-C3 alkyl, C1-C3 perfluoroalkyl, halo, cyano, or CO2 (C1-C3) alkyl.
3. A compound of claim 1 or 2, wherein R1 is methyl, ethyl, isopropyl, trifluoromethyl, bromo, chloro, cyano, or CO2methyl.
4. A compound of claim 3, wherein R1 is trifluoromethyl.
5. A compound of any one of claims 1 to 4, wherein R2 is C1-Ca alkyl, substituted C1-C3 alkyl, cyclohexyl, substituted cyclohexyl, piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, substituted tetrahydrothiopyranyl, or 1,4-dioxaspirodecanyl.
6. A compound of claim 5, wherein R2 is a piperidinyl group substituted with alkyl, alkoxycarbonyl, substituted alkylcarbonyl, substituted arylcarbonyl, substituted arylsulfonyl, alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, substituted arylaminothiocarbonyl, or substituted alkylaminothiocarbonyl .
7. A compound of claim 6, wherein R2 is a piperidinyl group substituted with alkyl, alkoxycarbonyl, carboxyalkylcarbonyl, cyanoarylcarbonyl, alkylarylcarbonyl, carboxyarylcarbonyl, alkoxycarbonylarylcarbonyl, carboxyarylsulfonyl, alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, carboxyarylaminothiocarbonyl, or alkoxycarbonylalkylaminothiocarbonyl.
8. A compound of claim 7, wherein R2 is a piperidinyl group substituted with methyl, ethoxycarbonyl, tertbutyloxycarbonyl, carboxypropylcarbonyl, methoxycarbonylphenylcarbonyl, carboxyphenylcarbonyl, cyanophenylcarbonyl, tertbutylphenylcarbonyl, carboxyphenylsulfonyl, methoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, carboxyphenylaminothiocarbonyl, or methoxycarbonylmethyleneaminothiocarbonyl.
9. A compound of any one of claims 1 to 5, wherein R2 is an alkyl group substituted with alkoxy, heterocycloalkyl, aryl, substituted aryl, heteroaryl, cyano, hydroxyl, or hydroxysulfonyl.
10. A compound of claim 9, wherein R2 is an alkyl group substituted with methoxy, morpholinyl, piperidinyl, thiomorpholinyl, tetrahydropyranyl, phenyl, carboxy phenyl, pyridyl, imidazolyl, benzoimidazolyl, cyano, hydroxyl, or hydroxysulfonyl.
11. A compound of any one of claims 1 to 5, wherein R2 is a cyclohexyl group substituted with hydroxyl, oxo, or alkyloxycarbonylamino.
12. A compound of claim 1 1, wherein R2 is a cyclohexyl group substituted with hydroxyl, oxo, or tertbutyloxycarbonylamino.
13. A compound of any one of claims 1 to 5, wherein R2 is a tetrahydrofuranyl group substituted with an oxo group.
14. A compound of any one of claims 1 to 5, wherein R2 is a tetrahydrothiopyranyl group substituted with an oxo group.
15. A compound of any one of claims 1 to 5, wherein R2 is a pyrrolidinyl group substituted with an arylalkyl group.
16. A compound of claim 15, wherein R2 is a pyrrolidinyl group substituted with a phenylmethyl group.
17. A compound of any one of claims 1 to 16, wherein R3 is phenyl or substituted phenyl.
18. A compound of claim 17, wherein R3 is phenyl.
19. A compound of claim 1, wherein R1 is methyl, ethyl, isopropyl, trifluoromethyl, bromo, chloro, cyano, or CO∑methyl; R2 is C1-C3 alkyl, substituted C1-C3 alkyl, cyclohexyl, substituted cyclohexyl, piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, substituted tetrahydrothiopyranyl, or 1 ,4-dioxaspirodecanyl; and R3 is phenyl or substituted phenyl.
20. A compound of claim 1 that is:
1 -(phenyl sulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)- 1 H-indole-3 -sulfonamide;
3-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyO-l//-indol-3-yl]sulfonyl}amino)piperidin- l-yl]sulfonyl}benzoic acid; methyl 4-{[4-({[l -(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoate;
4-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl } amino)piperidin- 1 -yl]carbonyl } benzoic acid; methyl N-{[4-({ [l-φhenylsulfonyl^-Ctrifluoromethyty-lH-indol-S- yl]sulfonyl}amino)piperidin-l-yl]carbonothioyl}glycinate;
N-(2-oxotetrahydrofuran-3-yl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole- 3- sulfonamide;
5-oxo-5-[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- y I ]sulfonyl } amino)piperidin- 1 -y 1 Jpentanoic acid;
4-[2-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)ethyl]benzoic acid; N-(trans-4-aminocyclohexyl)-l -(phenyl sulfonyl)-4-(trifluorom ethyl)- 1 H-indole-3- sulfonamide; l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)-4-(trifluoromethyl)-lH- indole-3- sulfonamide;
N-(1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)- 1 -(pheny lsulfonyl)-4- (trifluoromethyl)- lH-indole-3-sulfonamide;
N-(l-oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsulfonyl)-4-(trifluoromethyl)- IH- indole-3-sulfonamide;
N-ttrans^-hydroxycyclohexyO-l^phenylsulfonyl^-^rifluoromethyO-lH-indole- S- sulfonamide;
N-(4-oxocyclohexyl)-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide;
N-l,4-dioxaspiro[4.5]dec-8-yl-l -(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole- 3- sulfonamide; l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide; methyl oxo[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetate; oxo[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]acetic acid; l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide; l^phenylsulfonyO-N^-pyridin^-ylethyO^trifluoromethyO-lH-indole-S-sulfonamide; l-(phenylsulfonyl)-N-(pyridin-3-ylmethyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide; l-(phenylsulfonyl)-N-pyrrolidin-3-yl-4-(trifluoromethyl)-lH-indole-3-sulfonamide; l-(phenylsulfonyl)-N-(pyridin-4-ylmethyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide; l-(phenylsulfonyl)-N-(tetrahydro-2//-pyran-4-ylmethyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide; l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-4-(trifluoromethyl)-lH-indole-3-sulfonamide; tert-buty\ 4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate;
N-[(3/?)-l-benzylpyrrolidin-3-yl]-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide; tert-butyl [trans-4-({ [ 1 -(phenylsulfonyl)-4-(trifluoromethyl)- 1 H-indol-3- yl]sulfonyl}amino)cyclohexyl]carbamate;
4-{[3-[(piperidin-4-ylamino)sulfonyl]-4-(trifluoromethyl)-lH-indol-l- yl]sulfonyl}benzoic acid;
3-( { [ 1 -(phenyl sulfony l)-4-(trifluoromethyl)- lH-indol-3-yl Jsulfony 1 } ami no)propane- 1 - sulfonic acid; l-CphenylsulfonyO-N^^^.ό-tetramethylpiperidin^-yl^-^fluoromethyO-lH-indole- 3-sulfonamide;
N-cyclohexyl-l-(phenylsulfonyl)-4-(trifluoromethyI)-lH-indole-3-sulfonamide; iV-[2-(lH-benzimidazol-2-yl)ethyl]-l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indole-3- sulfonamide;
5-[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l-yl]-5- oxopentanoic acid;
N-^rα/zs^-hydroxycyclohexyO^-isopropyl-l-Cphenylsulfony^-lH-indole-S- sulfonamide;
/ert-butyl 4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine- 1-carboχylate;
4-isopropyl-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide;
3-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid;
4-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid;
4-isopropyl-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-thiopyran-4-yl)-lH-indole-3- sulfonamide;
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-4-isopropyl-l-(phenylsulfonyl)-lH-indole- 3-sulfonamide;
4-isopropyl-N-(l-oxidotetrahydro-2H-thiopyran-4-yl)-l-(phenylsulfonyl)-lH-indole-3- sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;;
N-P-ClH-imidazol-l-yOpropylJ^-isopropyl-l-Cphenylsulfony^-lH-indole-S- sulfonamide 4-isopropyl-N-(2-moφholin-4-ylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-isopropyl-N-(2-phenylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide; ethyl 4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl }amino)piperidine-l - carboxylate;
4-isopropyl-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-isopropyl- 1 -(phenylsulfonyl)-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]- 1 H-indole-3- sulfonamide;
4-i sopropyl- 1 -(phenyl sulfony l)-N-(tetrahydro-2H-pyran-4-yl methyl)- 1 H-indol e-3- sulfonamide;
N-benzyl-4-isopropyl-l -(phenylsulfonyl)- lH-indole-3-suIfonamide;
4-isopropyl -N-(3-phenylpropyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
3-({[4-({[4-isopropyl-l -(phenylsulfonyl)- lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]carbonothioyl}amino)benzoic acid;
N-(2-hydroxy-2-py ri din-3 -y 1 ethyl )-4-i sopropyl - 1 -(phenyl sulfony I)- 1 H-i ndol e-3 - sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-(2-thiomoφholin-4-ylethyl)-lH-indole-3-sulfonamide,
4-isopropyl-Ν-(l-methylpiperidin-4-yl)-l-(phenylsulfonyl)-lΗ-indole-3-sulfonamide; methyl 4-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin- 1 -y 1 ] carbony 1 } benzoate ;
4-bromo-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide; tert-butyl 4-({ [4-bromo- 1 -(phenylsulfonyl)- 1 H-indol-3-yl]sulfonyl }amino)piperidine-l - carboxylate;
4-bromo-l-(phenylsuIfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide;
4-bromo-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide;
4-bromo-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-bromo-l-(phenylsulfonyl)-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-lH-indole-3- sulfonamide;
4-bromo-N-(2-phenylethyl)-l -(phenylsulfonyl)- lH-indole-3-sulfonamide;
4-bromo-N-[l-(4-cyanobenzoyl)piperidin-4-yl]-l-(phenylsulfonyl)-lH-indole-3- sulfonamide;
4-ethyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide; 4-ethyl-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
/ert-butyl 4-({[4-ethyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-ethyl-l-(phenylsulfonyl)-iV-piperidin-4-yl-lH-indole-3-sulfonamide;
4-ethyl-l-(phenylsulfonyl)-iV-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide;
4-ethyl-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonaraide;
4-methyl-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-iV-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
4-methyl-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH-indole-3- sulfonamide;
4-chl oro- 1 -(phenyl sulfony l)-N-(tetrahy dro-2H-py ran-4-yl methyl)- 1 H-indole-3 - sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide; ethyl 4-({[4-chJoro-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-lH-indole-3-sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-chloro-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-chloro-N-(cyanomethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
Ν-[l-(4-tert-butylbenzoyl)piperidin-4-yl]-4-cyano-l-(phenylsulfonyl)-lΗ-indole-3- sulfonamide;
4-cyano-l-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-sulfonamide;
/er/-butyl 4-({[4-cyano-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidine-l- carboxylate;
4-cyano-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide;
4-cyano-l-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-lH-indole-3-sulfonamide;
4-cyano-N-(2-methoxyethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-cyano-N-(2-moφholin-4-ylethyl)-l-(phenylsulfonyl)-lH-indole-3-sulfonamide;
4-cyano- 1 -(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)- lH-indole-3-sulfonamide; 4-cyano-l-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-lH-indole-3-sulfonamide;
4-cyano-l-(phenylsulfonyl)-N-(2-piperidin-l-ylethyl)-lH-indole-3-sulfonamide;
4-chloro- 1 -(phenyl sulfonyl)-N-(2-piperidi n- 1 -ylethyl)- lH-indole-3-sulfonamide;
4-[2-({[4-(methoxycarbonyl)-l-(phenylsulfonyl)-lH-indol-3- yl]sulfonyl}amino)ethyl]benzoic acid; methyl l-(phenylsulfonyl)-3-{[(2-pyridin-3-ylethyl)amino]sulfonyl}-lH-indole-4- carboxylate; methyl l-(phenylsulfonyl)-3-{[(2-pyridin-4-ylethyl)amino]sulfonyl}-lH-indole-4- carboxylate; methyl 3-{[(fra«.s-4-hydroxycyclohexyl)amino]sulfonyl }-l -(phenylsulfonyl)-lH-indole- 4-carboxylate; or
4-isopropyl-l-(phenylsulfonyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-lH-indole-3- sulfonamide.
21. A compound of claim 1 that is: l-(phenylsulfonyl)-Ν-piperidin-4-yl-4-(trifluoromethyl)-lΗ-indole-3-sulfonamide;
3-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidin- l-yl]sulfonyl}benzoic acid;
4-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lΗ-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonyl}benzoic acid; methyl N-{[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]carbonothioyl}glycinate;
N-CZ-oxotetrahydrofuran-S-yO-l-Cphenylsulfonyl^-CtrifluoromethyO-lH-indole- S- sulfonamide;
5-oxo-5-[4-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidin-l-yl]pentanoic acid;
4-[2-({[l-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)ethyl]benzoic acid;
N-Orans^-aminocyclohexyO-l^phenylsulfony^^-ftrifluoromethyO-lH-indole-S- sulfonamide;
5-[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l-yl]-5- oxopentanoic acid; N-(/ira/7s-4-hydroxycyclohexyl)-4-isopropyl-l-(phenylsulfonyl)-lH-indole-3- sulfonamide;
4-isopropyl-l-(phenylsulfonyl)-N-piperidin-4-yl-lH-indole-3-sulfonamide; or 3-{[4-({[4-isopropyl-l-(phenylsulfonyl)-lH-indol-3-yl]sulfonyl}amino)piperidin-l- yl]sulfonyl}benzoic acid.
22. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, diluents, or carriers.
23. A method for treating a patient suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, prostate cancer, or Graves ophthalmopathy, and combinations thereof, or a patient in need of wound healing, comprising administering to the patient a therapeutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 21.
24. The method of claim 23 wherein the patient suffers from osteoporosis or arthritis.
25. A process for the preparation of a compound of formula (I):
I wherein:
R1 is alkyl, perfluoroalkyl, halo, cyano, or CO∑alkyl;
R2 is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, or spiroheterocycloalkyl; and
26. The process of claim 25, wherein the compound of formula IA is prepared by: contacting chlorosulfonic acid with a compound of formula IB:
IB; and optionally, further reacting the chlorosulfonic acid contacted compound of formula IB with PCl5.
27. The process of claim 26, wherein the compound of formula IB is prepared by: contacting R3-Sθ2-Cl with a compound of formula IC:
IC.
28. The process of claim 27, wherein the compound of formula IC is synthesized by:
(a) contacting a N,N-dimethylformamide dimethyl acetal with a compound of formula
BD:
29. The process of claim 28, wherein the reducing metal is iron and the acid is acetic acid.
30. A compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R4 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl;
R5 is hydrogen or alkyl;
R6 is optionally substituted aryl or heteroaryl;
R7 is alkyl, pcrfluoroalkyl, halo, cyano, or alkoxycarbonyl; and
X is absent or SO2.
31. A compound of claim 30, wherein X is SO2.
32. A compound of claim 30, wherein X is absent.
33. A compound of any one of claims 30 to 32, wherein R4 is optionally substituted cycloalkyl or heterocycloalkyl.
34. A compound of claim 33, wherein R4 is optionally substituted heterocycloalkyl.
35. A compound of claim 34, wherein R4 is optionally substituted piperidinyl.
36. A compound of any one of claims 30 to 32, wherein R4 is an alkyl, cycloalkyl, or heterocycloalkyl group optionally substituted with alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted arylsulfonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl , dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylsulfonyl, optionally substituted heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylsulfonyl or perfluoroalky lcarbonyl .
37. A compound of claim 36, wherein the arylcarbonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, and hetercycloalkylcarbonyl substituents for the alkyl, cycloalkyl, and heterocycloalkyl groups of R4 are optionally substituted with 1 to 5 substituents independently selected from alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, oxo, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl.
38. A compound of claim 36, wherein R4 is alkyl, cycloalkyl, or heterocycloalkyl optionally substituted with tertbutyloxy, trifluoromethylcarbonyl, tertbutyloxycarbonyl, trifiuoromethylsulfonyl, dimethylaminosulfonyl, or carboxyphenylsulfonyl.
39. A compound of any one of claims 30 to 38, wherein R5 is hydrogen, methyl, ethyl, propyl, or isopropyl.
40. A compound of claim 39, wherein R5 is hydrogen or methyl.
41. A compound of any one of claims 30 to 40, wherein R6 is aryl.
42. A compound of claim 41, wherein R6 is phenyl.
43. A compound of any one of claims 30 to 42, wherein R7 is C1-Cs alkyl, C1-Cs perfluoroalkyl, halo, cyano, or CCh(C 1-C3)alkyl.
44. A compound of claim 43, wherein R7 is methyl, ethyl, isopropyl, trifluoromethyl, bromo, chloro, cyano, or CO2CH3.
45. A compound of claim 44, wherein R7 is trifluoromethyl.
46. A compound of any one of claims 30 to 32, wherein R4 is optionally substituted heterocycloalkyl; R5 is hydrogen, methyl, ethyl, or propyl; R6 is phenyl; and R7 is methyl, ethyl, isopropyl, trifluoromethyl, bromo, chloro, cyano, or CO2CH3.
47. A compound of claim 30 that is: te/Y-Butyl 4-({[7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate;
7-(Phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH-indole-3-sulfonamide;
7-(Phenylsulfonyl)-N-[l-(trifluoroacetyl)piperidin-4-yl]-4-(trifluoromethyl)-lH-indole-3- sulfonamide;
N-[l-(2,2-Dimethylpropanoyl)piperidin-4-yl]-7-(phenylsulfonyl)-4-(trifluoromethyl)-lH- indole-3-sulfonamide;
N-{l-[(Dimethylamino)sulfonyl]piperidin-4-yl}-7-(phenylsulfonyl)-4-(trifluoromethyl)- 1 H-i ndole-3-sul fonam i de;
3-{[4-({[7-(Phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3-yl]sulfonyl}amino)piperidin- l-yl]sulfonyl}benzoic acid;
7-(Phenylsulfonyl)-4-(trifluoromethyl)-iV-{l-[(trifluoromethyl)sulfonyl]piperidin-4-yl}- 1 H-i ndole-3 -sulfonamide; tert-Butyl 4-({[l-methyl-7-(phenylsulfonyl)-4-(trifluoromethyl)-lH-indol-3- yl]sulfonyl}amino)piperidine-l-carboxylate; or l-Methyl-7-(phenylsulfonyl)-N-piperidin-4-yl-4-(trifluoromethyl)-lH-indole-3- sulfonamide.
48. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 30 to 47.
49. A method for treating a patient suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, prostate cancer, or Graves ophthalmopathy, and combinations thereof, or a patient in need of wound healing, comprising administering to the patient a therapeutically effective amount of at least one compound of formula (II) according to any one of claims 30 to 47.
50. The method of claim 49 wherein the patient suffers from osteoporosis or arthritis.
51. A process for the preparation of a compound of formula IIA:
R4 is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl; R6 is optionally substituted aryl or heteroaryl; R7 is alkyl, perfluoroalkyl, halo, cyano, or alkoxycarbonyl; and X is absent or SO2;
ITB.
52. The process of claim 51, further comprising reacting the compound of formula HA with a compound of formula: RA-R5, to form a compound of formula II:
II wherein,
RΛ is an activating group ; and
R5 is alkyl or substituted alkyl.
53. The process of claim 52, wherein RA is Cl, Br, I, tosylate, mesylate, triflate, an ester, an epoxide or an aldehyde
54. The process of any one of claims 51 to 53, wherein the compound of formula KB is prepared by: contacting sulfonyl chloride with a compound of formula EIC:
55. The process of claim 54, further comprising reacting the sulfonyl chloride contacted compound of formula UC with PCI5.
56. The process of claim 54, wherein the compound of formula IIC is prepared by: reacting vinylmagnesium bromide with a compound of formula IID:
ITD.
57. The process of claim 56, wherein the compound of formula HD is prepared by: reacting RB-X-R6 with a compound of formula IEE:
HE wherein, hal is halogen; and if X is SO2 then RB is hydrogen or if X is absent then RB is a boronic acid.
58. A compound of any one of claims 1-21 or 30-47 for use in the treatment of osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, prostate cancer, or Graves ophthalmopathy.
59. Use of a compound of any one of claims 1-21 or 30-47 in the preparation of a medicament for the treatment of osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, prostate cancer, or Graves ophthalmopathy.
60. Use of a compound according to claim 58 for the treatment of osteoporosis or arthritis.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US10004730B2 (en) | 2011-10-12 | 2018-06-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecules targeting androgen receptor nuclear localization and/or level in prostate cancer |
US10544110B2 (en) | 2013-09-20 | 2020-01-28 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer |
US10882834B2 (en) | 2013-09-20 | 2021-01-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compounds for treating prostate cancer |
CN112375027A (en) * | 2020-12-07 | 2021-02-19 | 中国药科大学 | Indolesulfonamide derivative and medical application thereof |
US10980806B2 (en) | 2016-03-24 | 2021-04-20 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014300A2 (en) * | 2002-08-09 | 2004-02-19 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
WO2005040114A1 (en) * | 2003-10-14 | 2005-05-06 | Oxagen Limited | Compounds having crth2 antagonist activity |
-
2007
- 2007-11-09 WO PCT/US2007/084245 patent/WO2008060998A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014300A2 (en) * | 2002-08-09 | 2004-02-19 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
WO2005040114A1 (en) * | 2003-10-14 | 2005-05-06 | Oxagen Limited | Compounds having crth2 antagonist activity |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10004730B2 (en) | 2011-10-12 | 2018-06-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecules targeting androgen receptor nuclear localization and/or level in prostate cancer |
US10544110B2 (en) | 2013-09-20 | 2020-01-28 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer |
US10882834B2 (en) | 2013-09-20 | 2021-01-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compounds for treating prostate cancer |
US10980806B2 (en) | 2016-03-24 | 2021-04-20 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer |
US11766433B2 (en) | 2016-03-24 | 2023-09-26 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer |
CN112375027A (en) * | 2020-12-07 | 2021-02-19 | 中国药科大学 | Indolesulfonamide derivative and medical application thereof |
CN112375027B (en) * | 2020-12-07 | 2023-03-31 | 中国药科大学 | Indolesulfonamide derivative and medical application thereof |
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