NZ613873B2 - Substituted aromatic sulfur compounds and methods of their use - Google Patents

Substituted aromatic sulfur compounds and methods of their use Download PDF

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Publication number
NZ613873B2
NZ613873B2 NZ613873A NZ61387312A NZ613873B2 NZ 613873 B2 NZ613873 B2 NZ 613873B2 NZ 613873 A NZ613873 A NZ 613873A NZ 61387312 A NZ61387312 A NZ 61387312A NZ 613873 B2 NZ613873 B2 NZ 613873B2
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NZ
New Zealand
Prior art keywords
phenyl
ethenesulfonyl
cyano
isobutyramide
substituted
Prior art date
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NZ613873A
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NZ613873A (en
Inventor
Bruce Dorsey
Scott K Kuwada
Jay P Theroff
Craig A Zificsak
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Cephalon Inc
University Of Hawaii
University Of Utah Research Foundation
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Application filed by Cephalon Inc, University Of Hawaii, University Of Utah Research Foundation filed Critical Cephalon Inc
Priority claimed from PCT/US2012/026274 external-priority patent/WO2012116151A2/en
Publication of NZ613873A publication Critical patent/NZ613873A/en
Publication of NZ613873B2 publication Critical patent/NZ613873B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
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    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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    • C07C2601/14—The ring being saturated
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    • C07C317/00—Sulfones; Sulfoxides
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/70—Sulfur atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Vinyl -Aryl - Sulfone Compounds of formula II are described, wherein A is as defined herein and attached at the 3 or 4 position, along with pharmaceutical compositions and methods of using compounds of formula II for treating or reducing the risk of peritoneal carcinomatosis in a patient. compounds of the disclosure include: 2-[3-((E)-2-Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy-phenyl)-isobutyramide; and; (E)-3-{4-[1-Methyl-1-(5-methyl-benzoxazol-2-yl)-ethyl]-benzenesulfonyl}-acrylonitrile. The disclosed compounds are particularly useful in reducing the risk of peritoneal carcinomatosis in a patient that has had an intra-abdominal cancer removed, the intra-abdominal cancer may be one of: colon, ovary, rectal, stomach or pancreas cancer. of the disclosure include: 2-[3-((E)-2-Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy-phenyl)-isobutyramide; and; (E)-3-{4-[1-Methyl-1-(5-methyl-benzoxazol-2-yl)-ethyl]-benzenesulfonyl}-acrylonitrile. The disclosed compounds are particularly useful in reducing the risk of peritoneal carcinomatosis in a patient that has had an intra-abdominal cancer removed, the intra-abdominal cancer may be one of: colon, ovary, rectal, stomach or pancreas cancer.

Description

SUBSTITUTED AROMATIC SULFUR COMPOUNDS AND METHODS OF THEIR USE TECHNICAL FIELD The present invention is directed to substituted aromatic sulfur compounds and methods of using them for the treatment and prevention of cancer, in particular, peritoneal carcinomatosis.
BACKGROUND Peritoneal carcinomatosis is a fatal form of metastasis that occurs when intra- abdominal cancers invade into the peritoneal cavity and attach to the peritoneum, a resilient tissue lining the abdominal cavity and its internal organs. Peritoneal carcinomatosis can also occur following surgical resections of intra-abdominal cancers, which releases cancer cells, blood, and lymph into the peritoneal cavity. In patients with gastric cancers, the neum and liver are the major sites of recurrence following ed lymphadenectomy (Maruyama et al. World J Surg 1987, 11: 418-25; Kaibara et al. Am J Surg 1990, 159: ; Korenaga et al. Surg Gynecol Obstet 1992, 174: 387- 93). Following ion of ovarian cancers, the most frequent site of recurrence is the peritoneal cavity (Armstrong et al. NEJM 2006, 354: 34-43).
Locoregional recurrence within the nal cavity is the first site of recurrence following resection of c cancers in approximately 50% of patients (Sugarbaker et al.
Seminars in al Oncology 2003, 21: 233-248). The evidence that intra-abdominal locoregional recurrence impacts patient survival comes from multiple s g that the recurrent gastric cancers remain confined to the abdominal cavity even at the time of death in many cases (Gunderson et al. Int J Radiat Oncol Biol Phys 1992, 8: 1-11; Wisbeck et al. Radiother Oncol 1986, 7: 13-18; Landry et al. Int J Radiat Oncol Biol Phys 1990: 1357-1362).
Other intra-abdominal malignancies, notably pseudomyxoma peritonei, appendiceal carcinoma, and mesothelioma, commonly result in peritoneal carcinomatosis as well.
The hallmarks of cancer are invasion and metastasis. Metastasis occurs most commonly when cancer cells gain entrance into the tic or hematogenous vessels through which they travel and then exit within capillary beds in secondary tissues. The rate-limiting step in metastasis is when circulating cancer cells re-adhere to tissues in secondary sites. It is well known that patients with advanced cancers often have high levels of circulating cancer cells. During surgical resections of advanced ancies, there is often a transient increase in circulating cancer cells as well. High levels of circulating cancer cells portend poorer survival due to the metastatic potential of the circulating cells.
Most women who undergo resection of ovarian cancer experience recurrence in the peritoneal cavity with ic dissemination much less commonly. A recent large randomized trial comparing intravenous and intraperitoneal paclitaxel (total of 6 cycles every 3 weeks) in women with stage III ovarian cancer showed an increase in long-term survival of 15.9 months for women who ed intraperitoneal chemotherapy (Armstrong et al. New England Journal of Medicine 2006, 354: 34-43). This improvement in survival occurred despite the fact that only 42% of patients completed all 6 cycles of herapy. These results led the NCI to e intraperitoneal therapy as the recommended management strategy for optimally debulked ovarian cancer.
As such, improved and more effective compounds and methods for the treatment and prevention of neal carcinomatosis are .
International Publication Number WC 2009/124272 A2 discloses methods of inhibiting proliferation of cancer cells, readhesion of cancer cells and other methods employing inhibitors B and activators of INK, along with nds useful therefor.
SUMMARY The present invention is directed to compounds of formula II, or pharmaceutically able salt forms thereof: D—S(O)n / Ra 11, where D, n, Ra, Rb, and R0 are as defined herein. ceutical compositions comprising compounds of formula II, or ceutically acceptable salt forms thereof, are also described. The invention also encompasses methods of using the compounds of formula II, or pharmaceutically acceptable salt forms thereof DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The present invention is directed to compounds of formula II, or pharmaceutically acceptable salt forms thereof: Ra 11 wherein: D is / / A2 A2 N A2 N a a 3 I ll A2 A2 8 , ; n is 0, l or 2; Ra is en, alkyl or phenyl; Rb is hydrogen, cyano, alkyl, phenyl, carbamoyl, or alkoxycarbonyl; RC is hydrogen, cyano, alkyl, phenyl, carbamoyl or alkyoxycarbonyl; A1 and A2 are, independently, hydrogen, 6 R d R9 R3%< k Re Re R2 R1 R2 R1 Rf Rf O Rh R9 | or ; where QisOor S; R1 and R2 are each independently substituted or unsubstituted alkyl or R1 and R2, together with the carbon atom to which they are attached, form a three- to seven-membered substituted or unsubstituted lkyl ring, or R1 and R2, together with the carbon atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl group; R3 is —OH, tuted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or tituted cycloalkalkyl, substituted or unsubstituted alkoxy, tuted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl; or -NR4R5; R4 and R5 are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted l, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylene oxide, substituted or unsubstituted cycloalkyl, substituted or tituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, - COOalkyl, -COalkyl, -COcycloalkyl, -NHCOalkyl, ryl, or -NHCOcycloalkyl; or R4 and R5, together with the atoms through which they are attached, form a substituted or unsubstituted cycloalkyl ring; R6 is substituted or unsubstituted alkyl, tuted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; Rd is substituted or tituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or tuted or unsubstituted heteroaralkyl; Re and Rf are, independently substituted or unsubstituted alkyl, or Re and Rf, together with the carbon atom to which they are attached, form a three- to seven-membered substituted or unsubstituted cycloalkyl ring, or R6 and Rf, er with the carbon atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl group; Rg is —OH, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lkalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, tuted or unsubstituted heterocycloalkylalkyl; or -NR4R5; and Rh is H, substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl; provided that one of A1 or A2 is other than hydrogen; and provided further that when D is 2 n is 2, and Ra, RC and A1 are hydrogen, and Rb is cyano, then A2 is other than tert-butyl.
An embodiment of the present invention is directed to nds of formula II, or pharmaceutically acceptable salt forms thereof, wherein D is U If m/ / A2 A2 N N A2 , ’ .
Another embodiment of the present invention is directed to compounds of formula II, or pharmaceutically acceptable salt forms f, wherein D is. _ _ 2 Another embodiment of the t invention is directed to compounds of formula A2 N/ 11, or pharmaceutically acceptable salt forms thereof, wherein D is Another embodiment of the present invention is directed to compounds of formula II, or pharmaceutically acceptable salt forms thereof, n D is Another embodiment of the present invention is directed compounds of formula II, or pharmaceutically able salt forms f, wherein Q is O.
A preferred embodiment of the present invention is directed to compounds according \\ ,IO D/ WON to compounds the a wherein D is as defined herein.
The designation for the value of D which is 2 8 indicates that the substituents Aland A2 are at the 3 and 2 positions of the thiophene ring, respectively, and that the sulfur containing side chain may be at either the 4 or 5 position of the thiophene ring, The designation for the value of D which is _ 6 _ 2 tes that the sulfur containing s1de chain is at the 2- position of the naphthalene ring, while the substiuents A1 and A2 may be at either the 5, 6, 7 or 8 positions of the naphthalene ring, 8 1 DC37 2 A25 4 Another embodiment of the present invention is directed to compounds of formula I, or pharmaceutically acceptable salt forms thereof: 2 0$840 4orWA// wherein A is at the 3- or 4- position of the phenyl ring; and Rflwé— R6 Ais R2 R1 orR2 R1 R1 and R2 are each independently substituted or tituted alkyl or R1 and R2, together with the carbon atom to which they are attached, form a three- to seven- membered substituted or unsubstituted cycloalkyl ring R3 is —OH, substituted or tituted alkyl, substituted or unsubstituted lkyl, substituted or unsubstituted cycloalkalkyl, tuted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, or -NR4R5; R4 and R5 are each independently H, substituted or tituted alkyl, substituted or unsubstituted alkyene oxide, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or tituted aralkyl, -COOalkyl, yl, -COcycloalkyl, -NHCOalkyl, -NHCOaryl, or -NHCOcycloalkyl; or R4 and R5, er with the atoms through which they are attached, form a substituted or unsubstituted heterocycloalkyl ring; and R6 is substituted or unsubstituted heteroaryl.
Pharmaceutical compositions comprising a compound of formula I or II, or a pharmaceutically acceptable salt form thereof, are also within the scope of the invention.
The compounds of the invention, as well as pharmaceutical compositions comprising compounds of the invention, are useful for treating or reducing the risk of peritoneal carcinomatosis in patients. In particular, the compounds are useful for treating or reducing the risk of peritoneal carcinomatosis in patients wherein an intra-abdominal cancer is surgically removed from the patient and a pharmaceutical composition comprising a nd of a I or II, or a pharmaceutically acceptable salt form thereof, is administered to the t.
Accordingly, the present invention provides a method of treating or ng the risk of peritoneal carcinomatosis in a patient that has had an intra-abdominal cancer removed, said method comprising administering to said patient a therapeutically effective amount of a compound of the present invention. In an embodiment of the invention the intra-abdominal cancer is located at or near the colon, at or near the ovary, at or near the rectum, at or near the stomach, or at or near the pancreas of the patient. r, the present invention provides a use of a compound of the t invention for ng or reducing the risk of peritoneal carcinomatosis is a patient that has had an intra-abdominal cancer removed. In an embodiment of the invention the intra- abdominal cancer is located at or near the colon, at or near the ovary, at or near the rectum, at or near the stomach, or at or near the as of the patient.
Further, the present invention provides for the use of a nd of the present invention for the manufacture of a medicament for treating or reducing the risk of peritoneal carcinomatosis is a patient that has had an abdominal cancer removed. In an embodiment of the invention, the intra-abdominal cancer is located at or near the colon, at or near the ovary, at or near the rectum, at or near the stomach, or at or near the pancreas of the patient.
In preferred ments of the invention, A of formula I is at the 4-position of the phenyl ring. In other embodiments, A is at the 3-position of the phenyl ring.
Preferred compounds of the invention include those wherein A is R956?R2 R1 In these embodiments, R1 and R2 ofA are preferably each independently substituted or unsubstituted alkyl, for example, -CH3. In other embodiments, R1 and R2, together with the carbon atom to which they are attached, form a three- to seven- membered substituted or unsubstituted cycloalkyl ring, for example, cyclopropyl or cyclobutyl.
Raki- In those embodiments wherein A is R2 R1 is —OH. In other , preferably, R3 embodiments, R3 is substituted or tituted alkyl. In yet other embodiments, R3 is tuted or unsubstituted cycloalkyl. In still other embodiments, R3 is substituted or unsubstituted cycloalkalkyl. In further embodiments, R3 is tuted or tituted alkoxy. In additional embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is substituted or unsubstituted heteroaryl. In yet other embodiments, R3 is substituted or unsubstituted cycloalkyl. In still other embodiments, R3 is substituted or tituted heterocycloalkylalkyl. dekré- In other preferred embodiments n A is R2 R1 is preferably - , R3 NR4R5. Preferred embodiments include those wherein R4 is hydrogen. In other embodiments, R4 is unsubstituted alkyl, for example, -CH3. 9ng— In preferred embodiments n A is R2 R1 and R3 is -NR4R5, R5 is hydrogen. In other embodiments, R5 is preferably tuted or unsubstituted alkyl. In other embodiments, R5 is substituted or unsubstituted aryl. In yet other embodiments, R5 is substituted or unsubstituted aralkyl. In still other embodiments, R5 is substituted or unsubstituted heteroaryl. In some embodiments, R5 is substituted or unsubstituted heteroaralkyl. In other embodiments, R5 is substituted or unsubstituted cycloalkyl. In r ments, R5 is substituted or unsubstituted heterocycloalkyl. In additional embodiments, R5 is substituted or tituted alkyene oxide. In other embodiments, R5 is ycloalkyl. In other embodiments, R5 is —COOalkyl. In yet other embodiments, R5 is —COall<yl. In further ments, R5 is —NHCOalkyl. In additional embodiments, R5 is —NHCOaryl.
RQKF; In still other embodiments n A is R2 R1 and R3 is -NR4R5, wherein R4 and R5, together with the atoms through which they are ed, form a substituted or unsubstituted heterocycloalkyl ring, for example, substituted or tituted morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted tetrahydroisoquinolinyl, or substituted or unsubstituted piperidinyl.
In other embodiments, A is R2 R1 . In these embodiments, R1 and R2 are each independently substituted or unsubstituted alkyl, for example, -CH3. Alternatively, R1 and R2, together with the carbon atom to which they are ed, form a three- to seven- membered substituted or unsubstituted cycloalkyl ring, for e, cyclopropyl or cyclobutyl.
In those embodiments wherein A is R2 R1 is a substituted or unsubstituted , R6 heteroaryl, for example, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted benzoimidazolyl, substituted or unsubstituted benzooxazolyl, or substituted or unsubstituted oxazolyl.
As used herein, the term “alkyl” refers to branched or unbranched saturated hydrocarbon chain. Examples include, but are not limited to, methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, and the like. Alkyl groups typically contain l-lO carbon atoms, ably 1-6 or 1-3 carbon atoms, and can be substituted or unsubstituted.
As used herein, the term “alkenyl” refers to an “alkyl” group containing the requisite number of carbon atoms as described herein for “alkyl”, and which contains at least one double bond. Representative examples of alkenyl groups include, but are not limited to ethenyl, allyl, isopropenyl, and 2-methyl-l-propenyl.
As used , the term “alkylene” refers to a divalent alkyl radical. es include, but are not limited to, methylene, ethylene, propylene, and the like.
As used herein, the term “alkoxy” refers to —O-alkyl groups, wherein alkyl is as defined herein.
As used , the term “alkoxycarbonyl” refers to an alkyl-O(C=O)- group.
As used herein, the term “alkynyl” refers to an “alkyl” group containing the requisite number of carbon atoms as bed herein for “alkyl”, and which contains at least one triple bond. Representative examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and l- and 2- butynyl.
As used herein, the term “aryl” refers to a phenyl or naphthyl group.
As used herein, the term “aralkyl” refers to an aryl group, as defined herein, bonded directly through an alkylene moiety. The alkylene moiety can have from 1-10 carbon atoms, ably 1-6 carbon atoms, more preferably 1 or 2 carbon atoms. In addition, the alkylene moiety of the l group can be unsubstituted or substituted. In tuted alkylene embodiments, the substitutent can be any of the substituents defined herein and is preferably —OH, -NH2, alkylene-OH, or alkyl.
As used herein, the term “alkylene oxide” refers to an alkylene group wherein one or more of the methylene units of the alkylene group has been replaced with an oxygen atom.
As used herein, the “carbamoyl” refers to a NH2C(=O)- group.
As used herein, the term “cycloalkyl” refers to a mono or bicyclic carbocyclic ring. es include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eptyl, bicyclo[2.2.l]heptanyl, and the like. Cycloalkyl groups typically contain 3- 12 carbon atoms, preferably 3-6 carbon atoms.
As used herein, the term alkalkyl” refers to a cycloalkyl group, as defined herein, bonded directly through an ne moiety. The alkylene moiety can have from 1-10 carbon atoms, preferably 1-6 carbon atoms, more preferably 1 or 2 carbon atoms. In addition, the alkylene moiety of the cycloalkalkyl group can be unsubstituted or substituted. In substituted alkylene embodiments, the substitutent can be any of the substituents defined herein and is preferably —OH, -NH2, or alkyl.
As used herein, the term “heterocycloalkyl” refers to a mono or bicyclic carbocyclic ring containing from 1 to 5 N, O, or S atoms. Examples include, but are not d to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, isoxazolidinyl, l,3-oxazolidinyl, isothiazolidinyl, 1,2- pyrazolindinyl, l,3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, morpholinyl, 1,2- tetrahydrothiazinyl, piperazinyl, and the like. One of ordinary skill in the art will understand that the connection of the heterocycloalkyl ring can be h a carbon atom or through a nitrogen heteroatom, Where possible. The term “heterocycloalkyl” also includes those mono or bicyclic carbocyclic rings containing a —NH-CO- group, for example, pyrrolidinylone, piperidinylone, and azepanylone.
Included Within the definition of “heterocycloalkyl” are fused ring systems, ing, for example, ring systems in which an aryl or heteroaryl ring is fused to a heterocycloalkyl ring. Examples include indoline, isoindoline, chorman, and isochroman, As used herein, the term “heterocycloalkalkyl” refers to a heterocycloalkyl group, as defined herein, bonded directly through an alkylene moiety. The alkylene moiety can have from 1-10 carbon atoms, preferably 1-6 carbon atoms, more preferably 1 or 2 carbon atoms. In on, the alkylene moiety of the cycloalkalkyl group can be unsubstituted or substituted. In tuted alkylene ments, the substitutent can be any of the substituents d herein and is preferably —OH, -NH2, or alkyl.
As used herein, the term oaryl” refers to refers to an aromatic group containing 5 to 10 ring carbon atoms in which one or more ring carbon atoms are replaced by at least one hetero atom such as -O-, -N-, or -S-. Examples of heteroaryl groups include pyrrolyl, filryl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxathiolyl, oxadiazolyl, lyl, oxatriazolyl, furazanyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, picolinyl, l, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, purinyl, quinazolinyl, quinolyl, isoquinolyl, benzoimidazolyl, benzothiazolyl, benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, phthalazinyl, yridinyl, and alinyl.
As used , the term “heteroaralkyl” refers to a heteroaryl group, as defined herein, bonded directly through an alkylene moiety. The alkylene moiety can have from 1-10 carbon atoms, preferably 1-6 carbon atoms, more preferably 1 or 2 carbon atoms. In addition, the alkylene moiety of the aralkyl group can be unsubstituted or substituted. In substituted alkylene ments, the substitutent can be any of the substituents defined herein and is preferably —OH, -NH2, or alkyl.
As used herein, the term “halogen” refers to fluorine, chlorine, bromine, and iodine.
As used , the term “substituted” or “substituent” refers to the substitution of any 1, 2, or 3 hydrogens by l, 2, or 3 onal . These onal groups include, but are not limited to, -OH, -CN, -CECH; , -COOH, -NH2, -NHalkyl, -NHaryl, - NHC(O)Oalkyl, -NHC(O)alkyl, )cycloalkyl, halogen, alkyl, cycloalkyl, heteroaryl, alkoxy, alkylene-OH, alkylene oxide, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -SOzalkyl, -SOz-NH2, Halkyl, and -SOz-NHaryl.
Compounds of the invention will be administered to a patient in a “therapeutically effective .” As used herein, a “therapeutically effective amount” refers to an amount of a compound of the invention effective to t, treat, or reduce the incidence of the claimed disease or disorder. The determination of the eutically effective amount will depend on several factors, including the age and weight of the patient, as well as the disease or disorder to be treated. Such a determination is within the skill of those in the art.
As used herein, “pharmaceutically acceptable carrier or diluent” refers to solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride. Pharmaceutically acceptable carriers may further include auxiliary substances such as wetting or emulsifying agents, preservatives, and buffers.
As used herein, “pharmaceutical composition” refers to a composition suitable for administration in medical or veterinary use. Such compounds will preferably include a nd of the invention in combination with one or more carriers and/or diluents.
As used herein, “administering” refers to any means within the art by which compounds of the invention can be delivered to the patient. Preferred administration methods e local administration, that is, administration of the compounds of the invention directly to the location where the effect of the nds is desired, and systemic administration. Examples of administration methods include, but are not limited to, oral, c, sublingual, sublavial, aneous, nasal, intravenous, intraarterial, intramuscular, and intraperitoneal administration. Preferred methods include local administration of a compound of the invention to the site of treatment, for example, the peritoneal cavity, via a spray or wash.
The present invention includes ceutically acceptable salts of compounds of formula I. Pharmaceutically acceptable acid addition salts of the compounds of formula I include, but are not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, and phosphorus, as well as the salts d from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts thus e, but are not limited to, sulfate, pyrosulfate, bisulfate, sulf1te, bisulf1te, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, ate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, e, maleate, tartrate, and methanesulfonate. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., "Pharmaceutical Salts," J. of Pharmaceutical e, 6:1-19.
The acid addition salts of the basic compounds may be ed by contacting the free base form with a sufficient amount of the d acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional . The free base forms differ from their respective salt forms somewhat in certain physical properties such as lity in polar solvents, but otherwise the salts are in general lent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts of compounds of formula I are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. es of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. es of suitable amines include, but are not limited to, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N—methylglucamine, and procaine; see, for example, Berge et al., supra., 1977. _ 14 _ The base addition salts of acidic compounds may be prepared by ting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be rated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms at in certain physical properties such as solubility in polar solvents, but otherwise the salts are in general equivalent to their respective free acid for purposes of the present ion.
Some of the compounds in the present invention may exist as stereoisomers, including enantiomers, diastereomers, and geometric isomers. Geometric isomers include nds of the present invention that have alkenyl groups, which may exist as entgegen (E) or zusammen (Z) conformations, in which case all geometric forms thereof, both entgegen and zusammen, cis and trans, and es thereof, are within the scope of the present invention. Some compounds of the t invention have cycloalkyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures thereof, are within the scope of the present ion. All of these forms, including (R), (S), s, reomers, cis, trans, syn, anti, (E), (Z), tautomers, and mixtures thereof, are contemplated in the compounds of the present invention.
The compounds to be used in the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are lent to unsolvated forms and are intended to be encompassed within the scope of the present invention The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below as well as using methods known to one skilled in the art of organic chemistry or variations thereon as appreciated by those skilled in the art. The preferred methods include, but are not limited to or by, those described below. Unless otherwise stated, starting and intermediate compounds are of commercial origin or readily synthesized by standard s well known to one skilled in the art of organic synthesis.
The compounds of this invention may be prepared using the reactions and techniques described in this section. The ons are performed in solvents appropriate to the reagents, and materials employed are suitable for the ormations being effected.
Also, in the description of the synthetic methods below, it is to be understood that all ed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and workup procedures are chosen to be conditions standard for that on which should be readily recognized by one skilled in the art of organic sis.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. Specific chemical ormations are listed in the ensuing schemes and one skilled in the art appreciates that a variety of different reagents may be used in place of those listed. Common replacements for such reagents can be found in, but not limited to, texts such as “Encyclopedia of Reagents for Organic Synthesis” Leo A. Paquette John Wiley & Son Ltd (1995) or “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” Richard C. Larock. Wiley-VCH and “Strategic Applications ofNamed Reactions in Organic Synthesis” Kurti and Czako, Elsevier, 2005 and references therein.
Scheme 1 NC X \ so Li 1/ O”s//O/ \ 2 \ \/\CN | X 1. BuLi or PhLi, THF | | Yfa/ / / 2' 802 2 Yfl<R R1 2 Yfl<R2 R1 R1 Ia NC X 8020 802Na \ \ 1/ | Nazszog, H20 | X Yfl</ Yq</ R2 R2 R1 R1 Compounds of formula Ia, for example where Y, R1 and R2 are, for example, alkyl, can be ed as set forth in Scheme 1. In a first step, an aryl halide such as — romobenzene is treated with an alkyl- or aryllithium reagent such as n-butyllithium -l6- or phenyllithium in an aprotic solvent such as tetrahydrofuran or ether. The newly formed organometallic species is quenched with sulfur dioxide to fiamish the sulfinic acid, which is isolated by filtration as the lithium salt. Alternatively, a phenylsulfonylchloride, such as 3-tert—butylphenylsulfonylchloride is d with sodium sulfite in water to prepare the 3- tert—butylphenylsulfinic acid sodium salt. The lithium or sodium sulfinic acid salt is treated with a substituted l,2-dihaloethane reagent (i.e., where X is halo) to provide the arylsulfonylethylene compound of formula Ia.
Scheme2 O 0 Br NC CI \V/ 80le. \ \ \ S\/\CN . . jl/ | 1. PhLI then BuLI, THF / | | 2. 802 / HOOC R2 LiOOC/KR2 Rz R1 R1 R1 lb Similarly, compounds of formula 1b, where R1 and R2 are, for example, alkyl, may be prepared as shown in Scheme 2. For example, romophenyl)isobutyric acid or 2- (3 -bromophenyl)isobutyric acid is treated with phenyl lithium followed by n-butyllithium then quenched with sulfur e to furnish the dilithium salt. The dilithium salt is reacted with 2-chloroacrylonitrile in a mixture of water:methanol:acetic acid. Once addition of the sulfinic acid to the 2-chloroacrylonitrile is complete, aqueous workup is followed by treatment with an amine base such as triethylamine to afford ation of the chloride and ion of the sulfonylacrylonitrile of formula Ib.
Scheme3 O\\ //O O\\ //O @SN/Nm NHR4R5 \ 8%CN O | HOOCV(/ coupling agent R5R4NH/ R1R2 R1R2 For the ation of amides of the general formula Ic, as shown in Scheme 3, and, for example, where R1 and R2 are methyl, either 2-[4-((E)cyano-ethenesulfonyl)- phenyl]methyl- propionic acid or 2-[3-((E)cyano-ethenesulfonyl)-phenyl]methyl- propionic acid prepared as in Scheme 2 may be reacted with a primary or ary amine, where R4 and R5 are as defined herein, or are synthetic precursors thereto, in the presence of an amide ng reagent in an aprotic solvent such as dichloromethane, _ 17 _ tetrahydrofuran, dimethylformamide, and the like. Examples of suitable amide coupling reagents include carbodiimides (e.g. dicyclohexylcarbodiimide or N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), phosphonium salts (e.g. (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or bromotripyrrolidinophosphonium hexafluorophosphate), propylphosphonic ide, and the like. Following amide bond formation, the compounds are readily isolated by purification on silica gel or by reverse-phase HPLC.
Scheme4 H H O\\80/4 R’ \[81/ \NH2 \O\\8/40 coupling agent H0007<R2 RHN—<O)4 Id The ion of the heterocyclic derivative of the general a Id is shown in Scheme 4. R1 and R2 are as defined . R is a substituent as defined herein. Similar to a procedure known in the art itski Checkler, E. L.; Elokdah, H. M.; , J.
Tetrahedron Lett. 2008, 49, 6709.), for example 1 and R2 are methyl, reaction of 2- [4-((E)cyano-ethenesulfonyl)-phenyl]methyl- propionic acid or 2-[3-((E)cyanoethenesulfonyl )-phenyl]methyl- propionic acid with thiosemicarbazides in the presence of a coupling agent, for example N—(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride furnishes the 2-substituted amino-l,3,4-oxadiazoles of general formula Id.
Scheme 5 O\\S//O NH2 0 o S\/\CN J “H/ \\s/’/ 4R: 0 O R2 AcOH \ S\/\CN coupling agent \ / IN I R1 R2 JH The formation of benzimidazole or benzoxazole compounds of general formula Ie, where J is O or NR4, where R4 as defined herein, R1 and R2 are as defined herein, and R is one or more substituents as defined herein, is shown in Scheme 5. The formation begins with an amide coupling as described in Scheme 3, followed by heating the 2-hydroxy- or 2-amino-phenylamide in the presence of acetic acid to furnish the benzoxazole or benzimidazole compound of general formula Ie.
Scheme 6 0“s/’\/\ 0/8 NH2 O\\ x/0 o 0 CN ;/ \\ // R2 RO\ O/M R \ S\/\CN HOOC ng agent NH/ —3"\_(\|N I OH/ R1 R1 R2 If lg Scheme 6 describes the preparation of e derivatives of general formula If, where R1 and R2 are as defined herein and R is a substituent as defined herein. A propargylic amine is d to a carboxylic acid to furnish a gylic amide of general formula If by means of an amide coupling as described in Scheme 3. Treatment of the propargylic amide with catalytic gold(III) chloride in acetonitrile by methods known in the art (Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.) furnishes the cycloisomerized product of general formula Ig.
Scheme 7 H2NNH OS\\//0 R\ENH O O S\/\CN R\(0 \\S/\/\CN\ / O\\S//O/ NH/ -H20 \ N\ wCN HOOC7<R2 coupling agent R% I R1 R2 0%IN R1 Compounds of general a Ij, where R1 and R2 are as defined herein and R is a substituent as defined herein may be prepared from, for example, (E)cyano- ethenesulfonyl)-phenyl]methyl- propionic acid or 2-[3-((E)cyano-ethenesulfonyl)- ]methyl- propionic acid, by coupling with an acyl hydrazide in the presence of N—(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or other suitable amide coupling reagent in a polar c solvent such as acetonitrile to afford the acylhydrazide of general formula Ii. 2-Substituted-l,3,4-oxadiazoles of general formula Ij may be prepared from the acylhydrazide by dehydration, which may be accomplished with a reagent such as phosphorous oxychloride, thionyl chloride or Burgess’ reagent, with or without the presence of a polar or non-polar, aprotic solvent, such as acetonitrile or dioxane.
Preventing the implantation of rogue cancer cells within the peritoneum is al to preventing metastasis and fithher disease development.
NF-kB ar factor kappa B) is ently but strongly activated during the adhesion of adenocarcinoma cells (Scaife et al. Cancer Research 2002, 62: 6870-78).
Treatment of suspended adenocarcinoma cells with compounds of the ion resulted in an induction of apoptosis during adhesion. In a peritoneal carcinomatosis model in mice, pretreatment 4 hours before IP injection of human colon and pancreatic adenocarcinoma cells followed by 3 more treatments over 9 days with nds of the invention (e.g., 1 mg/kg) significantly inhibited peritoneal tumor implantation. Compounds of the invention also inhibited colon cancer cell proliferation (e.g., 10 uM) and colon cancer afts in athymic mice.
Compounds of the invention target multiple s in cancer cells. Compounds of the invention inhibit IKK-mediated phosphorylation of IkB, the endogenous inhibitor of NF-kB, but activate JNK and p3 8/SAPK as well (Pierce et al. J Biol Chem 1999). It has now been shown that JNK activation is important for the tic activity of compounds of the invention in human colon and pancreatic cancer cells. Furthermore, JNK activation targets FLIP (FLICE inhibitory protein) for degradation in cancer cells. FLICE (caspase 8) is commonly overexpressed in cancers and a critical mediator of death receptor - d apoptosis. FLIP sion is ted by NF-kB and treatment of cancer cells with compounds of the invention rapidly decreases FLIP expression in a INK-dependent fashion. Inhibition of FLIP expression in colon and pancreatic cancer cells enhanced the ability of compounds of the invention to induce apoptosis of the cells during adhesion while overexpression of FLIP in colon and pancreatic cancer cells rendered them resistant to the apoptotic effects of compounds of the invention. It has thus been determined that the apoptotic activity in cancer cells of the compounds of the invention requires the dual activities on NF-kB and JNK.
The results of testing certain compounds of the invention against various cell lines is shown in Table I below. SU86 is a pancreatic cancer cell line. HT29 is a colon cancer cell line. BxPC3 is a pancreatic cell line. A2780 is an ovarian cancer cell line.
Table I _ 20 _ nd BXPC3 A2780 ”M **** **** **** **** **** nd A2780 ”M **** **** **** **** **** nd A2780 ”M nd A2780 ”M nd A2780 ”M nd BXPC3 A2780 ”M **** **** **** **** **** nd A2780 ”M **** **** **** nd A2780 ”M **** **** **** **** **** Compound * = <lO% ve reduction in Luciferase activity ** = 10-50% relative reduction in Luciferase activity *** = 50-85% relative reduction in Luciferase activity **** = >85% relative reduction in Luciferase activity EXPERIMENTAL SECTION All reagents and solvents were obtained from commercial sources and used as received. 1H-NMR spectra were obtained on a Bruker Avance at 400 MHz in the solvent indicated with tetramethylsilane as an internal standard. Analytical HPLC was run using a Zorbax Eclipse XDB-C8 3.5 um 4.6x75 mm column eluting with a mixture of acetonitrile and water containing 0.1% trifluoroacetic acid with a 5 minute gradient of 10-100%.
LCMS results were obtained on either of two instruments. A Waters Aquity Ultra Performance LC with a Waters Aquity UPLC BEH C18 l.7 um 2. 1x50 mm column was paired with a ass-ZQ 2000 quadrupole mass spectrometer with electrospray tion. Alternatively, an Agilent 1100 series HPLC with a Zorbax Eclipse XDB-C8 3.5 um 2. 1x30mm column was paired with a Bruker Esquire 3000 mass spectrometer with ospray tion. Preparative HPLC was performed on a Gilson HPLC using a Phenomenex Gemini NX 5 um C l 8, 2l .2x100 mm column with UV detection or a Waters HPLC using a Waters e PrepC8 5um OBD 30x75 mm column with MS detection on a Micromass-ZQ 2000 quadrupole mass spectrometer with electrospray ionization.
Automated column chromatography was performed on a CombiFlash Companion (Teledyne Isco Inc.). g points were taken on a Mel-Temp apparatus and are uncorrected.
Example 1 (E)Cyano-ethenesulfonyl)-phenyl]methyl- propionic acid 0\ ’O \S/ / O \/\\\N To a solution of 2-(4-bromophenyl)methylpropanoic acid (2.43 g, 10 mmol) in anhydrous THE (150 ml) under nitrogen at — 80 oC (ether/dry ice), was added slowly phenyl lithium in toluene (l .8 M, ll mmol). After 5 min, to this mixture, n-BuLi (2.5 M in hexane, ll mmol) was added. A cloudy suspension was slowly . Twenty minutes after BuLi addition, a stream of S02 was bubbled through the mixture for 15 min. The reaction e was then allowed to warm up to room temperature and the solvent was removed in vacuo. The sulfinate residue was dissolved in water (15 ml), acetic acid (8 ml), and MeOH (20 ml), followed by addition of 2-chloroacrylonitrile (18 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed in vacuo and the residue was diluted with 20 ml of water. The solution was adjusted to pH5 -6 with sat. K2HPO4 aq. solution then extracted with dichloromethane (2x100 ml) and dried over MgSO4. After filtration, the filtrate was stirred with ylamine (20 mmol) for 1 h. The solution was washed with 10% aq citric acid and brine, and then dried over MgSO4. The final t was purified by flash column chromatography (silica gel, dichloromethane/EtOAc, nt) to give 2-[4-((E)Cyanoethenesulfonyl )-phenyl]methyl- nic acid (1.2 g, 43%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) 5 12.65 (s, 1H), 8.23 (d, 1H, J = 15.6 Hz), 7.88 (m, 2H), 7.68 (m, 2H), 6.91 (d, 1H, J = 15.6 Hz), 1.51 (s, 6H); 13C—NMR: (DMSO-d6, 100 MHz) 8 176.7, 152.4, 149.1, 135.6, 128.2, 127.5, 114.6, 112.0, 46.4, 26.1.
Example 2 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]methyl- propionic acid O\\ 40 HO 8“N To a solution of 2-(3-bromophenyl)methylpropanoic acid (7.3 g, 30 mmol) in anhydrous THF (300 ml) under N2 at — 80 oC (ether/dry ice), was added slowly phenyl lithium in toluene (1.8 M, 33 mmol). After 5 min, to this mixture, n-BuLi (2.5 M in hexane, 33 mmol) was added. A cloudy suspension was slowly formed. Twenty minutes after BuLi addition, a stream of S02 was bubbled h the mixture for about 15 min.
The on mixture was then allowed to warm up to room temperature and the solvent was removed in vacuo. The sulfinate e was dissolved in water (50 ml), acetic acid (25 ml), and MeOH (50 ml), followed by on of 2-chloroacrylonitrile (60 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed in vacuo and the residue was diluted with 50 ml of water. The solution was adjusted to pH~5 -6 with sat. K2HPO4 aq. solution, then extracted with dichloromethane (2x100 mL) and dried over MgSO4. After filtration, the filtrate was stirred with triethylamine (20 mmol) for 1 h. The solution was washed with 10% aq. citric acid and brine, dried over MgSO4. The final product was purified by flash column chromatography (silica gel, dichloromethane/EtOAc, nt) to give 2-[3-((E)Cyano-ethenesulfonyl)- phenyl]methyl- propionic acid (4.1 g, 49%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) 5 12.65 (s, 1H), 8.30 (d, 1H, J = 15.6 Hz), 7.82 (m, 2H), 7.80 (m, 1H), 7.69 (m, 1H), 6.94 (d, 1H, J = 15.6 Hz), 1.53 (s, 6H); 13C—NMR: (DMSO-d6, 100 MHz) 8 176.8, 149.0, 147.2, 137.6, 132.7, 130.1, 126.4, 124.8, 114.6, 112.3, 46.1, 26.1.
(E)[4-(1 , 1 -Dimethylmorpholinyloxo-ethyl) -benzenesulfonyl]-acrylonitrile O“s”o/ O \V/A\$§N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (50.0 mg, 0.179 mmol), morpholine (0.0156 mL, 0.179 mmol), N-(3-dimethylaminopropyl)-N'- arbodiimide hydrochloride (34.3 mg, 0.179 mmol) and 1-hydroxybenzotriazole (12.1 mg, 0.0895 mmol) were dissolved in tetrahydrofuran (5.0 mL) and the on mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford [4-(1,1- Dimethylmorpholinyloxo-ethyl) -benzenesulfonyl]-acrylonitrile (11 mg, 17%).
MS: 349 (M+H); 1H-NMR (DMSO-d6 400 MHz) 5 8.24 (d, 1H, J = 15.7 Hz), 7.91 (d, 2H, J = 7.7 Hz), 7.55 (d, 2H, J = 7.7 Hz), 6.90 (d, 1H, J = 15.7 Hz), 3.57 (br s, 8H), 1.47 (s, 6H).
Example 4 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxy-ethyl)-isobutyramide o 8% H O\/\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), ethanolamine (0.0162 mL, 0.268 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in tetrahydrofuran (7.5 mL) and the reaction mixture was allowed to stir overnight at room ature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined ts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-(2-hydroxy-ethyl)-isobutyramide as a white foam (10 mg, 12%). MS: 323 (M+H); 1H-NMR (DMSO-d6, 400 MHz) 8 8.23 (d, 1H, J = 15.7 Hz), 7.85 (d, 2H, J = 7.4 Hz), 7.62 (d, 2H, J = 7.4 Hz), 7.45 (m, 1H), 6.90 (d, 1H, J = 15.7 Hz), 4.39 (t, 1H, J = 5.3 Hz), 3.40 (m, 2H), 3.11 (m, 2H), 1.47 (s, 6H).
Example 5 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-phenyl- isobutyramide O O \\ x, CLO ”\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (300.0 mg, 1.074 mmol), aniline 9 mL, 1.07 mmol), N—(3-dimethylaminopropyl)-N'- arbodiimide hydrochloride (206 mg, 1.07 mmol) and 1-hydroxybenzotriazole (72.6 mg, 0.537 mmol) were dissolved in tetrahydrofuran (30 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were ted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium e, filtered and concentrated.
The crude reaction e was purified by flash column (hexanes/ethyl acetate) to afford 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-phenyl- isobutyramide as a foam (171 mg, 45%). MS: 355 (M+H); 1H-NMR(DMSO-d6, 400 MHz) 8 9.22 (s, 1H), 8.23 (d, 1H, J: .7 Hz), 7.90 (d, 2H, J = 7.8 Hz), 7.68 (d, 2H, J = 7.8 Hz), 7.57 (d, 2H, J = 7.7 Hz), 7.27 (m, 2H), 7.05 (m, 1H), 6.90 (d, 1H, J = 15.7 Hz), 1.60 (s, 6H); 13C—NMR: (DMSO-d6, 100 MHz) 8 173.7, 153.2, 149.2, 139.0, 135.5, 128.4, 128.2, 127.6, 123.5, 120.4, 114.6, 112.0, 47.9, 26.5.
Example 6 N—Benzyl-2—[4-((E)cyano-ethenesulfonyl)-phenyl]- yramide O O \‘ ’/ o S\/\\\N (DAM 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (300.0 mg, 1.074 mmol), amine (0.115 g, 1.07 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (206 mg, 1.07 mmol) and 1-hydroxybenzotriazole (72.6 mg, 0.537 mmol) were dissolved in tetrahydrofuran (30 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated.
The crude on mixture was purified Via Isco flash column (hexanes/ethyl acetate) to afford N—Benzyl-2—[4-((E)—2-cyano-ethenesulfonyl)-phenyl]- isobutyramide as a white powder (173 mg, 44%). MS: 369 (M+H); 1H-NMR (DMSO-d6, 400 MHz) 8 8.24 (d, 1H, J = 15.6 Hz), 8.06 (t, 1H, J = 5.6 Hz), 7.86 (d, 2H, J = 7.6 Hz), 7.63 (d, 2H, J = 7.6 Hz), 7.27 (m, 2H), 7.21 (m, 1H), 7.11 (d, 2H, J = 7.3 Hz), 6.90 (d, 1H, J = 15.6 Hz), 4.24 (d, 2H, J = 5.6 Hz), 1.52 (s, 6H); 13C—NMR: (DMSO-d6, 100 MHz) 8 174.6, 153.4, 149.2, 139.6, 135.3, 128.0, 127.9, 127.6, 126.7, 126.5, 114.5, 111.9, 46.6, 42.3, 26.3.
Example 7 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-pyridin- 2-ylmethyl-isobutyramide \ N | H 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), pyridinyl-methylamine (0.0290 g, 0.268 mmol), N—(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (5 l .5 mg, 0.268 mmol) and l-hydroxybenzotriazole (18.1 mg, 0. 134 mmol) were dissolved in tetrahydrofuran (7.5 mL, 92 mmol) and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were ted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford 2-[4-((E)Cyanoethenesulfonyl yl]-N-pyridin- thyl-isobutyramide as a TFA salt (24 mg, 24%). MS: 370 (M+H); lH-NMR (DMSO-d6, 400 MHz) 8 8.63 (d, 1H, J = 4.8 Hz), 8.26 (m, 2H), 8.06 (t, 1H, J = 5.4 Hz), 7.89 (d, 2H, J = 8.1 Hz), 7.67 (d, 2H, J = 8.1 Hz), 7.54 (m, 1H), 7.35 (d, 1H, J = 7.8 Hz), 6.92 (d, 1H, J = 15.6 Hz), 4.43 (d, 2H, J = 5.4 Hz), 1.57 (s, 6H).
Example 8 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-isobutyl- isobutyramide O O \\’/ (E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), isobutylamine 5 mL, 0.268 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (5 l .5 mg, 0.268 mmol) and l-hydroxybenzotriazole (l 8.1 mg, 0. 134 mmol) were dissolved in tetrahydrofuran (7.5 mL) and the reaction mixture was allowed to stir ght at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-isobutyl- isobutyramide (18 mg, 20%). MS: 335 (M+H); 1H- NMR d6, 400 MHz) 8 8.23 (d, 1H, J = 15.9 Hz), 7.86 (d, 2H, J = 7.6 Hz), 7.61 (d, 2H, J = 7.6 Hz), 7.45 (m, 1H), 6.90 (d, 1H, J = 15.9 Hz), 2.84 (m, 2H), 1.67 (m, 1H), 1.48 (s, 6H), 0.74 (d, 6H, J = 6.6 Hz).
(E)-3 -{4-[1 ,1-Dimethyl(4-methyl-piperazinyl)- ethyl]-benzenesulfonyl} - nitrile O“s”o/ O \/\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 1-methylpiperazine (0.0298 mL, 0.268 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in tetrahydrofuran (7.5 mL) and the reaction mixture was allowed to stir ght at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford (E){4-[1,1- Dimethyl(4-methyl-piperazinyl)- 2-oxo-ethyl]-benzenesulfonyl} -acrylonitrile as a TFA salt (17 mg, 17%). MS: 362 (M+H); 1H-NMR (DMSO-d6, 400 MHz) 5 9.67 (br s, 1H), 8.25 (d, 1H, J = 15.8 Hz), 7.92 (d, 2H, J = 7.9 Hz), 7.56 (d, 2H, J = 7.9 Hz), 6.91 (d, 1H, J = 15.8 Hz), 3.53 (br s, 4H), 3.27 (br s, 2H), 2.84 (br s, 2H), 2.73 (s, 3H), 1.50 (s, 6H).
Example 10 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-cyclopropylmethyl- isobutyramide V/\NH 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (100.0 mg, 0.3580 mmol), cyclopropylmethylamine (0.0307 mL, 0.358 mmol), N—(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (68.6 mg, 0.358 mmol) and oxybenzotriazole (24.2 mg, 0.179 mmol) were dissolved in tetrahydrofuran (10 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium e, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-cyclopropylmethyl- isobutyramide as a foam (45 mg, 38%).
MS: 333 (M+H); 1H-NMR(CDC13, 400 MHz) 5 7.87 (d, 2H, J = 7.8 Hz), 7.63 (d, 2H, J = 7.8 Hz), 7.21 (d, 1H, J = 15.8 Hz), 6.55 (d, 1H, J = 15.8 Hz), 5.36 (br s, 1H), 3.10 (m, 2H), 1.61 (s, 6H), 0.87 (m, 1H), 0.47 (m, 2H), 0.15 (m, 2H).
Example 11 (E)Cyano-ethenesulfonyl)-phenyl]-N-(2,2-difluoro- ethyl)-isobutyramide O\\ /,O Y\NH 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (100.0 mg, 0.3580 mmol), 2,2-difluoro-ethylamine (0.0290 g, 0.358 mmol), imethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (68.6 mg, 0.358 mmol) and 1-hydroxybenzotriazole (24.2 mg, 0.179 mmol) were dissolved in tetrahydrofuran (10 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with romethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse _ 42 _ phase chromatography. Combined fractions were lyophilized to afford 2-[4-((E)Cyanoethenesulfonyl yl]-N-(2,2-difluoro- -isobutyramide as a white foam (40 mg, 32%). 1H-NMR(CDC13, 400 MHz) 5 7.89 (d, 2H, J = 7.6 Hz), 7.60 (d, 2H, J = 7.6 Hz), 7.23 (d, 1H, J = 15.7 Hz), 6.57 (d, 1H, J = 15.7 Hz), 5.84 (tt, 1H, J = 4.0, 56 Hz), 5.46 (m, 1H), 3.61 (m, 2H), 1.62 (s, 6H).
Example 12 (E)Cyano-ethenesulfonyl)-phenyl]-N-cyclohexyl- isobutyramide O O \\ x, (10 S/A 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (100 mg, 0.358 mmol), cyclohexanamine (35.5 mg, 0.358 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (68.6 mg, 0.358 mmol) and 1-hydroxybenzotriazole (24.2 mg, 0.179 mmol) were dissolved in tetrahydrofuran (10.0 mL) and the on mixture was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.2 mL of acetonitrile. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N- cyclohexyl- isobutyramide (79 mg, 61%), mp = 191-193 0C. MS: 361 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 7.86 (d, 2H, J = 8.1 Hz), 7.60 (d, 2H, J = 8.1 Hz), 7.21 (d, 1H, J = 15.6 Hz), 6.55 (d, 1H, J = 15.6 Hz), 5.05 (m, 1H), 3.76 (m, 1H), 1.83 (m, 2H), 1.64 (m, 3H), 1.62 (s, 6H), 1.34 (m, 2H), 1.13 (m, 1H), 1.00 (m, 2H).
Example 13 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(tetrahydro- pyranyl)-isobutyramide O 0 O 8/ O V\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (100.0 mg, 0.3580 mmol), tetrahydro-pyranylamine (0.0362 g, 0.358 mmol), N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (68.6 mg, 0.358 mmol) and l-hydroxybenzotriazole (24.2 mg, 0. 179 mmol) were dissolved in tetrahydrofuran (10 mL) and the reaction mixture was allowed to stir ght at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford 2-[4-((E)Cyanoethenesulfonyl )-phenyl]-N-(tetrahydro- pyranyl)-isobutyramide as a white powder (45 mg, 35%). MS: 363 (M+H); lH-NMR (CDCl3, 400 MHz) 5 7.87 (d, 2H, J = 7.6 Hz), 7.60 (d, 2H, J = 7.6 Hz), 7.21 (d, 1H, J = 15.6 Hz), 6.56 (d, 1H, J = 15.6 Hz), 5.08 (m, 1H), 3.98 (m, 1H), 3.90 (m, 2H), 3.44 (m, 2H), 1.83 (m, 2H), 1.59 (s, 6H), 1.34 (m, 2H).
Example 14 N—(4-Chloro-benzyl)[4-((E)cyano-ethenesulfonyl) -phenyl]-isobutyramide O\\ [’0 BAHN CI 2- [4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (100.0 mg, 0.3 5 80 mmol), robenzylamine (0.0507 g, 0.358 mmol), N—(3-dimethylaminopropyl)-N'- arbodiimide hydrochloride (68.6 mg, 0.358 mmol) and l-hydroxybenzotriazole (24.2 mg, 0. 179 mmol) were dissolved in tetrahydrofuran (10 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over ted sodium bicarbonate and organics were ted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. ed fractions were lized to afford N—(4-Chloro- benzyl)[4-((E)cyano-ethenesulfonyl) -phenyl]-isobutyramide as a white powder (69 mg, 48%). lH-NMR (CDCl3, 400 MHz) 5 7.86 (d, 2H, J = 7.4 Hz), 7.60 (d, 2H, J = 7.4 Hz), 7.27 (d, 2H, J = 7.4 Hz), 7.20 (d, 1H, J = 15.6 Hz), 7.11 (d, 2H, J = 7.4 Hz), 6.55 (d, 1H, J = 15.6 Hz), 5.53 (br s, 1H), 4.37 (d, 2H, J = 5.6 Hz), 1.62 (s, 6H).
Example 15 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-thiophen- 2-ylmethyl-isobutyramide O O O $§N 2- )Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (100.0 mg, 0.3 5 80 mmol), thiophenemethanamine (0.0405 g, 0.358 mmol), N—(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (68.6 mg, 0.358 mmol) and l-hydroxybenzotriazole (24.2 mg, 0.179 mmol) were dissolved in tetrahydrofuran (10 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lized to afford (E)Cyano- ethenesulfonyl)-phenyl]-N-thiophenylmethyl-isobutyramide as a white powder (67 mg, 50%). MS: 375 (M+H); lH-NMR (CDCl3, 400 MHz) 5 7.85 (d, 2H, J = 7.4 Hz), 7.60 (d, 2H, J = 7.4 Hz), 7.20 (m, 2H), 6.90 (m, 2H), 6.54 (d, 1H, J = 15.4 Hz), 5.55 (br s, 1H), 4.59 (d, 2H, J = 5.4 Hz), 1.62 (s, 6H).
Example 16 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-((S)-l - phenyl-ethyl)-isobutyramide 0° 00 E S\é7“\$§N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), (S)-l-phenyl-ethylamine (34.3 uL, 0.268 mmol), imethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (5 l .5 mg, 0.268 mmol) and l-hydroxybenzotriazole (l 8.1 mg, 0.134 mmol) were dissolved in ene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.3 mL of acetonitrile. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent afforded 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-((S) phenyl-ethyl)-isobutyramide as an amorphous white solid (66 mg, 64%). MS: 383 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 7.84 (d, 2H, J = 7.6 Hz), 7.55 (d, 2H, J = 7.6 Hz), 7.37-7.25 (m, 3H), 7.24-7.14 (m, 3H), 6.53 (d, 1H, J = 15.7 Hz), 5.59 (d, 1H, J = 7.1 Hz), .16-5.06 (m, 1H), 1.61 (s, 3H), 1.60 (s, 3H), 1.43 (d, 3H, J = 6.8 Hz).
Example 1 7 2- )Cyano-ethenesulfonyl)-phenyl]-N-((R) phenyl-ethyl)-isobutyramide o\\ ,[o 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), (R)phenyl-ethylamine (34.2 uL, 0.268 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.3 mL of itrile. ation by mass-directed HPLC using a gradient of 25-75% MeCN/water both ning 0.1% TFA as the eluting solvent afforded 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-((R) -ethyl)-isobutyramide as an amorphous white solid (69 mg, 67%). MS: 383 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 7.84 (d, 2H, J = 7.3 Hz), 7.54 (d, 2H, J = 7.3 Hz), 7.37-7.26 (m, 3H), 7.23-7.15 (m, 3H), 6.54 (d, 1H, J = 15.6 Hz), 5.68 (d, 1H, J = 6.8 Hz), .16-5.06 (m, 1H), 1.62 (s, 3H), 1.60 (s, 3H), 1.44 (d, 3H, J = 6.8 Hz).
Example 18 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4-fluoro- benzyl)-isobutyramide 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 4-fluoro-benzylamine (30.5 uL, 0.268 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the e was taken up in 1.2 mL of acetonitrile. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent afforded 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4- fluoro- benzyl)-isobutyramide as a white foam (34 mg, 34%). MS: 387 (M+H); 1H-NMR (CDCl3, 400 MHz) 8 7.85 (d, 2H, J = 7.4 Hz), 7.59 (d, 2H, J = 7.4 Hz), 7.30-7.24 (m, 1H), .10 (m, 2H), 7.04-6.95 (m, 2H), 6.55 (d, 1H, J = 15.6 Hz), 5.63-5.50 (m, 1H), 4.37 (d, 2H, J = 5.6 Hz), 1.63 (s, 6H).
Example 19 (E)Cyano-ethenesulfonyl)-phenyl]-N-prop ynyl-isobutyramide 0‘ 00 \S / O \/\\\N (E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (145 mg, 0.519 mmol), propynylamine (50.0 uL, 0.729 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (139 mg, 0.727 mmol) and 1-hydroxybenzotriazole (37 mg, 0.28 mmol) were combined in methylene chloride (3.00 mL). After 1h, the mixture was conc. to dryness. The residue was taken up in DMSO and purified (mass-directed HPLC, 15-55% MeCN:H20, TFA modifier) to afford 2-[4-((E)—2-Cyano-ethenesulfonyl)- phenyl]-N-prop ynyl-isobutyramide as an ite foam (66 mg, 40%). MS: 317 (M+H); 1H-NMR(CDC13, 400 MHz) 8 7.88 (d, 2H, J = 8.1 Hz), 7.61 (d, 2H, J = 8.1 Hz), 7.23 (d, 1H, J = 15.7 Hz), 6.56 (d, 1H, J = 15.7 Hz), 5.40 (s, 1H), 4.03 (m, 2H), 2.21 (s, 1H), 1.62 (s, 6H).
Example 20 (E)-3 - {4- [2-(3 ,4-Dihydro-1H-isoquinolinyl)-1,1-dimethyl- 2-oxo-ethyl]- esulfonyl} -acrylonitrile \\// O \/\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 1,2,3,4-tetrahydroisoquinoline (35.8 mg, 0.268 mmol), N—(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and l- ybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.2 mL of itrile. Purification by irected HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford (E){4-[2-(3,4- Dihydro-1H-isoquinolinyl)- 1 , 1 -dimethyl- 2-oxo-ethyl] -benzenesulfonyl} -acrylonitrile as a white solid (23 mg, 22%), mp = 54-60 0C. MS: 395 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 8.00-7.60 (m, 2H), 7.60-7.33 (m, 2H), 7.25-6.87 (m, 5H), 6.65-6.41 (m, 1H), .62 (m, 1H), 4.22-3.72 (m, 2H), 3.31-3.03 (m, 1H), 3.00-2.78 (m, 1H), 2.52-2.23 (m, 1H), 1.62 (s, 6H).
Example 21 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4-pyrazol- 1-yl-benzyl)-isobutyramide 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 4-Pyrazolyl-benzylamine (46.5 mg, 0.268 mmol), N—(3-dimethylaminopropyl)- ylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the reaction mixture was d to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.2 mL of itrile. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4- pyrazol- 1-yl-benzyl)-isobutyramide roacetic acid salt as a pale-yellow solid (33 mg, 28%), mp = 47-53 c’C. MS: 435 (M+H); 1H-NMR(CDC13, 400 MHz) 8 .83 (m, 3H), 7.80-7.76 (m, 1H), 7.64-7.57 (m, 4H), 7.30-7.25 (m, 2H), 7.21 (d, 1H, J = 15.6 Hz), 6.55 (d, 1H, J = 15.6 Hz), 6.52-6.47 (m, 1H), 5.73-5.63 (m, 1H), 4.44 (d, 2H, J = 5.7 Hz), 1.64 (s, 6H).
Example 22 N—Benzyl[4-((E)cyano-ethenesulfonyl)-phenyl]-N-methyl-isobutyramide O\\ 40 (E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), N—methyl-benzenemethanamine, (34.6 uL, 0.268 mmol), N—(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1- hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.2 mL of acetonitrile. Purification by mass-directed HPLC using a gradient of 25-75% _ 49 _ MeCN/water both containing 0.1% TFA as the eluting solvent to afford N—Benzyl[4- ((E)cyano-ethenesulfonyl)-phenyl]- N—methyl-isobutyramide as a white foam (33 mg, 32%). MS: 383 (M+H); 1H-NMR (CDC13, 400 MHz, mixture of rotamers) 8 7.92-7.76 (m, 2H), 7.49 (d, 2H, J = 8.0 Hz), 7.40-7.01 (m, 6H), 6.55 (d, 1H, J = 14.7 Hz), 4.72-3.94 (m, 2H), 3.02-2.31 (m, 3H), 1.63 (s, 6H).
Example 23 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4-methoxy- )-isobutyramide | o\ ,o o ‘s’ / OO V\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 4-methoxybenzenamine (33.1 mg, 0.268 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the on mixture was d to stir overnight at room temperature. The reaction was concentrated under d pressure and the residue was taken up in 1.2 mL of acetonitrile. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the g solvent to afford 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4- methoxy- phenyl)-isobutyramide as a white solid (53 mg, 52%), mp = 123-126 °C. MS: 385 (M+H); 1H-NMR (CDC13, 400 MHz) 8 7.90 (d, 2H, J = 8.2 Hz), 7.69 (d, 2H, J = 8.2 Hz), 7.28 (d, 2H, J = 8.6 Hz), 7.21 (d, 1H, J = 15.7 Hz), 6.83 (d, 2H, J = 8.6 Hz), 6.77 (bs, 1H), 6.57 (d, 1H, J = 15.7 Hz), 3.78 (s, 3H), 1.71 (s, 6H).
Example 24 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-phenethyl- isobutyramide O O \\ x, @0 8/WM 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), phenylethylamine (33.7 uL, 0.268 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure and the e was taken up in 1.2 mL of acetonitrile. Purification by mass-directed HPLC using a nt of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N- phenethyl- isobutyramide as a white foam (39 mg, 38%). MS: 383 (M+H); 1H-NMR (CDCl3, 400 MHz) 8 7.79 (d, 2H, J = 8.6 Hz), 7.49 (d, 2H, J = 8.6 Hz), 7.29-7.21 (m, 3H), 7.19 (d, 1H, J = 15.7 Hz), .02 (m, 2H), 6.55 (d, 1H, J = 15.7 Hz), 5.20-5.08 (m, 1H), 3.53-3.46 (m, 2H), 2.76 (t, 2H, J = 6.7 Hz), 1.54 (s, 6H).
Example 25 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy- phenyl)-isobutyramide O O \\ // Q0 \AN \o N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (150.0 mg, 0.5370 mmol), 3-methoxyaniline (80.3 uL, 0.715 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (143 mg, 0.745 mmol) and 1-hydroxybenzotriazole (36.1 mg, 0.267 mmol) were ved in acetonitrile (2.50 mL) and the reaction mixture was d to stir at room temperature overnight. The reaction was diluted with 0.4mL DMSO, filtered and purified. Purification by mass-directed HPLC using a gradient of 25- 75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E) Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy-phenyl)-isobutyramide (108 mg, 52.3%) as a white foam. MS: 385 (M+H); 1H-NMR(CDC13, 400 MHz) 5 7.91 (d, 2H, J = 8.5 Hz), 7.68 (d, 2H, J = 8.5 Hz), 7.25-7.16 (m, 3H), 6.86-6.78 (m, 2H), 6.67 (dd, 1H, J = 1.9, 8.3 Hz), 6.57 (d, 1H, J = 15.7 Hz), 3.79 (s, 3H), 1.71 (s, 6H).
Example 26 (E)Cyano-ethenesulfonyl)-phenyl]-N-(4-sulfamoyl- benzyl)-isobutyramide HZN/ “o 4-Aminomethyl-benzenesulfonamide hydrochloride (59.8 mg, 0.268 mmol) was placed in methylene de (10.00 mL) and macroporous carbonate resin (3.16 mmol/g loading, 255 mg, 0.806 mmol) was added. The reaction was stirred at room temperature for 30 minutes and then d to remove the resin. The solution was added to a vial containing 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol), and N—(3-dimethylaminopropyl)- N'-ethylcarbodiimide hloride (51.5 mg, 0.268 mmol). The reaction was stirred at 40 oC overnight and then concentrated under reduced pressure. The residue was taken up in 1.6 mL ofDMSO and purified by prep-HPLC using a gradient of 10-45% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-(4-sulfamoyl- benzyl)-isobutyramide as a white foam (17 mg, 14%). MS: 448 (M+H); lH-NMR (DMSO-d6, 400 MHz) 5 8.24 (d, 1H, J = 15.6 Hz), 8.16 (t, 1H, J = 5.8 Hz), 7.88 (d, 2H, J = 8.4 Hz), 7.73 (d, 2H, J = 8.1 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.35-7.26 (m, 4H), 6.91 (d, 1H, J = 15.6 Hz), 4.28 (d, 2H, J = 5.8 Hz), 1.52 (s, 6H).
Example 27 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4-methanesulfonyl- )—isobutyramide O O \x x, O\\ H 4-Methanesulfonyl-benzylamine hloride (59.5 mg, 0.268 mmol) was placed in methylene chloride (10.00 mL) and macroporous carbonate resin (3.16 mmol/g loading, 255 mg, 0.806 mmol) was added. The reaction was stirred at room temperature for 30 minutes and then filtered to remove the macroporous carbonate resin. The solution was added to a vial containing 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol), and N—(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol). The reaction was stirred at 40 OC overnight and was then concentrated under reduced pressure.
The residue was taken up in 1.6 mL ofDMSO and purified by prep-HPLC using a gradient of 10-45% MeCN/water both ning 0.1% TFA as the eluting t to afford 2-[4-((E)—2-Cyano-ethenesulfonyl)-phenyl]-N-(4-methanesulfonyl- benzyl)- isobutyramide as a white foam (33 mg, 28%). MS: 447 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 7.87 (d, 2H, J = 8.4 Hz), 7.80 (d, 2H, J = 8.2 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.2 Hz), 7.22 (d, 1H, J = 15.6 Hz), 6.57 (d, 1H, J = 15. 6 Hz), 5.99 (t, 1H, J = .6 Hz), 4.49 (d, 2H, J = 6.0 Hz), 3.03 (s, 3H), 1.66 (s, 6H).
Example 28 (E)-3 -[4-(1 , 1-Dimethyloxopiperidinyl-ethyl) -benzenesulfonyl]-acrylonitrile \\ // 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), piperidine (26.6 uL, 0.268 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in methylene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room ature. The reaction was trated under reduced pressure and the residue was taken up in 1.6 mL of DMSO. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford (E)[4-(1,1-Dimethyloxopiperidinyl-ethyl) - benzenesulfonyl]-acrylonitrile as a yellow oil (25 mg, 27%). MS: 347 (M+H); 1H-NMR , 400 MHz) 8 7.88 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.22 (d, 1H, J = .6 Hz), 6.56 (d, 1H, J = 15.6 Hz), 3.26-2.64 (m, 3H), 1.93-1.68 (m, 1H), 1.57 (s, 6H), 1.56-1.44 (m, 4H), .95 (m, 2H); 13C—NMR: (DMSO-d6, 100 MHz, 95 0C) 5 172.3, 153.9, 149.6, 135.7, 128.6, 126.4, 114.3, 111.5, 47.1, 45.1, 28.1, 24.9, 23.7.
Example 29 _ 53 _ 2- [4-((E)Cyano-ethenesulfonyl)-phenyl] ) hydroxyphenyl-ethyl)- isobutyramide O S\/\\\ N—(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (116 mg, 0.602 mmol) was added to 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (153 mg, 0.548 mmol), (S)aminophenyl-ethanol (86.0 mg, 0.627 mmol) and 1- hydroxybenzotriazole (6.8 mg, 0.050 mmol) in methylene chloride (6.0 mL) and stirred for 1h. The mixture was conc. in vacuo, ved in DMSO and purified (mass-directed HPLC, 15-55% MeCN/water, TFA modifier). Concentration of the product fractions afforded 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-((S)hydroxyphenyl-ethyl)- isobutyramide (143 mg, 65.5%) as a white foam. MS: 399 (M+H); 1H-NMR (DMSO-d6, 400 MHz) 8 8.25 (d, 1H, J = 15.6 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.25 (m, 2H), 7.17 (m, 3H), 6.91 (d, 1H, J = 15.6 Hz), 4.87 (m, 1H), 3.53 (d, 2H, J = 6.7 Hz), 1.51 (s, 6H). e 30 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-((S) oxo-azepanyl)-isobutyramide O\\ /,O o SV\\\N (S)—3-Amino-azepanone hydrochloride (44.2 mg, 0.268 mmol) was placed in methylene chloride (10.00 mL) and macroporous carbonate resin (3.16 mmol/g loading, 255 mg, 0.806 mmol) was added. The reaction was stirred at room temperature for 30 minutes and then filtered to remove the resin. The solution was added to a vial containing 2-[4-((E) ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 1- hydroxybenzotriazole (18.1 mg, 0.134 mmol), and N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol). The reaction was stirred at 40 CC overnight and was then trated under reduced pressure. The residue was taken up in 1.6 mL ofDMSO and purified by prep-HPLC using a gradient of 10-45% MeCN/water both containing 0.1% TFA as the eluting t to afford 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-((S) oxo-azepanyl)-isobutyramide (60 mg, 57%) as a white foam. MS: 390 (M+H); HNMR (DMSO-d6, 400 MHz) 5 8.23 (d, 1H, J = 15.6 Hz), 7.90-7.84 (m, 1H), 7.86 (d, 2H, J = 8.5 Hz), 7.69 (d, 2H, J = 6.5 Hz), 7.23 (d, 1H, J = 6.2 Hz), 6.90 (d, 1H, J = 15.6 Hz), 4.41-4.30 (m, 1H), 3.23-3.10 (m, 1H), 3.10-2.97 (m, 1H), 1.93-1.82 (m, 1H), 1.82-1.69 (m, 2H), 1.69-1.55 (m, 1H), 1.51 (s, 6H), 1.41-1.26 (m, 1H), 1.25-1.10 (m, 1H).
Example 31 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-[4-(2-methoxy- ethoxymethyl)-phenyl]- yramide | o\ ,o o ‘s’ / wonW\/\\\NN a) Potassium hydroxide (0.682 g, 10.3 mmol) was added to a suspension of p- nitrobenzylbromide (2.048 g, 9.480 mmol) in 2-methoxyethanol (20.0 mL, 254 mmol) and the mixture was heated in a vial at 105 0C. After 90 min, the e was cooled to room temperature. The mixture was poured into EtOAc (100 mL) and washed with water (3X10 mL), brine (20 mL) and dried over sodium sulfate. Concentration in vacuo after filtration gave an oil, which was d on ISCO (25g preload w/DCM, 80g column, 5-40% EtOAc:Hex). Pure fractions were combined and conc. to afford 1-(2-Methoxyethoxymethyl tro-benzene (1.245 g, 62.18%) as an orange oil. b) 1-(2-Methoxy-ethoxymethyl)nitro-benzene (200 mg, 0.947 mrnol was dissolved in methanol (9.5 mL) and 5% Platinum on Carbon, Sulfided (0.5%) (36.9 mg, 0.00947 mmol) was added. The reaction was hydrogenated at 50 psi for 60 minutes and then filtered through celite to remove the catalyst. The filtrate was then concentrated under d pressure to afford 4-(2-Methoxy-ethoxymethyl)-phenylamine as a yellow oil. c) 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 4-(2-Methoxy-ethoxymethyl)-phenylamine (48.7 mg, 0.268 mmol), N—(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1- hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in ene chloride (7.50 mL) and the reaction mixture was allowed to stir overnight at room temperature. The on was concentrated under reduced pressure and the e was taken up in 1.6 mL of DMSO. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-[4-(2-methoxy- ethoxymethyl)-phenyl]-isobutyramide as an orange oil (57 mg, 48%). MS: 465 (M+Na); HNMR d6, 400 MHz) 5 9.23 (s, 1H), 8.23 (d, 1H, J = 15.7 Hz), 7.89 (d, 2H, J = 8.6 Hz), 7.67 (d, 2H, J = 8.6 Hz), 7.54 (d, 2H, J = 8.6 Hz), 7.22 (d, 2H, J = 8.6 Hz), 6.0 (d, 1H, J = 15.7 Hz), 4.40 (s, 2H), .43 (m, 4H), 3.24 (s, 3H), 1.60 (s, 6H).
Example 32 (2- {2- [4-((E)Cyano-ethenesulfonyl)-phenyl]methyl- propionylamino} -ethyl)- ic acid tert-butyl ester o ,lo \V \\ H “\N OYNWNH 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (1.00E2 mg, 0.358 mmol), N-(2-aminoethyl)(tert-butoxy)carboxamide (62.3 uL, 0.394 mmol), and N,N— diisopropylethylamine (168 uL, 0.967 mmol) were placed in methylene chloride (3.00 mL) and bromotris(pyrrolydino)phophonium hexafluorophosphate (184 mg, 0.394 mmol) was added. The reaction was stirred at room temperature for 45 minutes and then concentrated under reduced pressure. The e was taken up in DMSO and purified by prep-HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford (2- {2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl- propionylamino}-ethyl)-carbamic acid tert—butyl ester as a white foam (101 mg, 67%).
MS: 444 (M+Na); HNMR (CDCl3, 400 MHz) 5 7.85 (d, 2H, J = 8.6 Hz), 7.61 (d, 2H, J = 8.6 Hz), 7.20 (d, 1H, J = 15.6 Hz), 6.77-6.66 (m, 1H), 6.53 (d, 1H, J = 15.6 Hz), 4.93-4.80 (m, 1H), 3.38-3.21 (m, 4H), 1.61 (s, 6H), 1.41 (s, 9H).
Example 33 (6- {2- [4-((E)Cyano-ethenesulfonyl)-phenyl] methyl- propionylamino} -hexyl)- carbamic acid tert-butyl ester l o\\S,/o/ \/\NHW“\N N—tert-Butyloxycarbonyl-l,6-diaminohexane hydrochloride (90.5 mg, 0.358 mmol) was placed in 5.0 mL ofDCM with 450 mg of macroporous carbonate resin (3 mmol/g) and stirred for 30 minutes and then filtered to remove the resin. 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]methyl-propionic acid (100 mg, 0.358 mmol), 1- hydroxybenzotriazole (24.2 mg, 0.179 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (68.6 mg, 0.358 mmol), and N,N—diisopropylethylamine (187 uL, 1.07 mmol) were placed in 5.0 mL ofDCM and the solution ofN—tertbutyloxycarbonyl-l ,6-diaminohexane was added. The on was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in 1.5 mL of DMSO and purified by Prep-HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the g solvent to afford (6- {2-[4-((E) Cyano-ethenesulfonyl)-phenyl]methyl- propionylamino} -hexyl)-carbamic acid tert- butyl ester as a white foam (119 mg, 70%). MS: 500 (M+H); HNMR , 400 MHz) 7.86 (d, 2H, J = 8.5 Hz), 7.61 (d, 2H, J = 8.5 Hz), 7.23 (d, 1H, J = 15.7 Hz), 6.56 (d, 1H, J = 15.7 Hz), 5.61-5.42 (m, 1H), 4.64-4.42 (m, 1H), 3.25-3.15 (m, 2H), 3.11-3.00 (m, 2H), 1.60 (s, 6H), .34 (m, 13H), 1.34-1.16 (m, 4H).
Example 34 {2- [2-(2- {2-[4-((E)Cyano-ethenesulfonyl)-phenyl] - 2-methyl-propionylamino} - ethoxy)-ethoxy]—ethyl} -carbamic acid tert-butyl ester O\\ [’0 \‘/ S / H \/\\\N O\n/N\/\O/\/O\/\NH 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (150 mg, 0.537 mmol), {2-[2-(2-amino-ethoxy)-ethoxy]-ethyl}-carbamic acid tert-butyl ester (147 mg, 0.591 mmol), N,N—diisopropylethylamine (252 uL, 1.45 mmol) were placed in methylene chloride (4.50 mL) and bromotris(pyrrolydino)phophonium hexafluorophosphate (275 mg, 0.591 mmol) was added. The reaction was stirred at room temperature for 45 s and then trated under reduced pressure. The residue was taken up in DMSO and purified by prep-HPLC using a gradient of 25-75% ater both containing 0.1% TFA as the eluting solvent to afford (2- {2-[4-((E)Cyano-ethenesulfonyl)-phenyl]- 2-methyl-propionylamino}-ethoxy)-ethoxy]-ethyl}-carbamic acid tert-butyl ester as an oil (214 mg, 78%). MS: 532 (M+Na); HNMR(CDC13, 400 MHz) 8 7.86 (d, 2H, J = 8.4 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.23 (d, 1H, J = 15.7 Hz), 6.55 (d, 1H, J =15.7 Hz), 5.83-5.30 (m, 2H), 3.60- 3.48 (m, 8H), 3.48-3.38 (m, 2H), 3.34-3.20 (m, 2H), 1.61 (s, 6H), 1.45 (s, 9H).
Example 35 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]-N-cyclohexyl-isobutyramide H 0“ 40 N S 0/ WM 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (83.0 mg, 0.297 mmol), cyclohexanamine (45.2 uL, 0.396 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (79.0 mg, 0.412 mmol) and oxybenzotriazole (20.0 mg, 0.148 mmol) were dissolved in acetonitrile (1.50 mL) and the reaction mixture was allowed to stir 1h at room temperature. The reaction was diluted with 0.4mL DMSO, filtered and purified. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[3-((E) Cyano-ethenesulfonyl)-phenyl]-N-cyclohexyl-isobutyramide (78 mg, 73%) as an off white foam. MS: 361 (M+H); 1H-NMR(DMSO-d6, 400 MHz) 8 8.25 (d, 1H, J = 15.6 Hz), 7.78 (m, 1H), 7.74 (m, 2H), 7.67 (m, 1H), 7.20 (d, 1H, J = 8.0 Hz), 6.90 (d, 1H, J = 15.6 Hz), 3.55 (m, 1H), 1.64 (m, 4H), 1.55 (m, 1H), 1.47 (s, 6H), 1.0-1.3 (m, 5H).
Example 36 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy-phenyl)-isobutyramide 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (83.0 mg, 0.297 mmol), 3-methoxyaniline (44.4 uL, 0.396 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (79.0 mg, 0.412 mmol) and 1-hydroxybenzotriazole (20.0 mg, 0.148 mmol) were dissolved in acetonitrile (1.50 mL) and the reaction mixture was allowed to stir 1h at room temperature. The reaction was diluted with 0.4mL DMSO, filtered and purified. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[3-((E) Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy-phenyl)-isobutyramide (29 mg, 25%) as a light pink lyophilate. MS: 385 (M+H); 1H-NMR d6, 400 MHz) 8 9.19 (s, 1H), 8.28 (d, 1H, J = 15.6 Hz), 7.85 (m, 1H), 7.82 (m, 1H), 7.77 (m, 1H), 7.70 (m, 1H), 7.25 (m, 1H), 7.16 (m, 2H), 6.91 (d, 1H, J = 15.6 Hz), 6.62 (m, 1H), 3.70 (s, 3H), 1.61 (s, 6H).
Example 37 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4-fiuoro-benzyl)-isobutyramide \©\/NH o 0 \\S//\/\\\ 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (83.0 mg, 0.297 mmol), 4-fiuoro-benzylamine (45.0 uL, 0.396 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (79.0 mg, 0.412 mmol) and 1-hydroxybenzotriazole (20.0 mg, 0.148 mmol) were dissolved in acetonitrile (1.50 mL) and the reaction mixture was allowed to stir 1h at room temperature. The reaction was diluted with 0.4mL DMSO, filtered and purified. Purification by irected HPLC using a gradient of 25-75% MeCN/water both ning 0.1% TFA as the eluting solvent afforded (E) Cyano-ethenesulfonyl)-phenyl]-N-(4-fiuoro-benzyl)-isobutyramide (61 mg, 53%) as a beige lyophilate. MS: 387 (M+H); 1H-NMR (DMSO-d6, 400 MHz) 5 8.25 (d, 1H, J = .6 Hz), 8.08 (m, 1H), 7.90 (m, 2H), 7.73 (m, 1H), 7.70 (m, 1H), 7.15 (m, 2H), 7.08 (m, 2H), 6.91 (d, 1H, J = 15.6 Hz), 4.22 (d, 2H, J = 6.0 Hz), 1.53 (s, 6H).
Example 3 8 N-(4-Amino-benzyl)[4-((E)cyano-ethenesulfonyl)-phenyl]-isobutyramide O O 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (83.0 mg, 0.297 mmol), 4-aminobenzylamine (44.8 uL, 0.396 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (79.0 mg, 0.412 mmol) and 1-hydroxybenzotriazole (20.0 mg, 0.148 mmol) were dissolved in acetonitrile (1.50 mL) and the reaction mixture was allowed to stir 1h at room temperature. The reaction was diluted with 0.4mL DMSO, filtered and purified. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford N-(4-Amino- benzyl)[4-((E)cyano-ethenesulfonyl)-phenyl]-isobutyramide roacetic acid salt (69 mg, 47%) as a white lyophilate. MS: 384 (M+H); 1H-NMR (DMSO-d6, 400 MHZ) 5 8.23 (d, 1H, J = 15.7 Hz), 8.05 (t, 1H, J = 5.9 Hz), 7.86 (d, 2H, J = 8.6 Hz), 7.62 (d, 2H, J = 8.6 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.02 (d, 2H, J = 8.4 Hz), 6.90 (d, 1H, J = 15.7 Hz), 4.35 (br s, 3H), 4.19 (d, 2H, J = 5.9 Hz), 1.51 (s, 6H).
Example 39 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(3-fiuoro-benzyl)—isobutyramide O\\ /,O o S\/\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 3-fiuorobenzylamine (30.6 uL, 0.268 mmol), imethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and oxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in itrile (1.00 mL) and the reaction mixture was d to stir for 2 hours at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.6 mL of DMSO. Purification by mass- directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(3-fluoro-benzyl)- isobutyramide (17 mg, 16%) as a white late. MS: 387 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 7.87 (d, 2H, J = 8.7 Hz), 7.61 (d, 2H, J = 8.7 Hz), 7.32-7.23 (m, 1H), 7.20 (d, 1H, J = 15.6 Hz), .91 (m, 2H), 6.84-6.78 (m, 1H), 6.55 (d, 1H, J = 15.6 Hz), 5.62- .49 (m, 1H), 4.40 (d, 2H, J = 5.9 Hz), 1.64 (s, 6H).
Example 40 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-fluoro-benzyl)-isobutyramide O O \\ // 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), obenzylamine (30.6 uL, 0.268 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in acetonitrile (1.00 mL) and the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.6 mL of DMSO. Purification by mass- directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-fluoro-benzyl)- yramide (40 mg, 38%) as a white lyophilate. MS: 387 (M+H); 1H-NMR (CDCl3, 400 MHz) 8 7.83 (d, 2H, J = 8.7 Hz), 7.56 (d, 2H, J = 8.7 Hz), 7.31-7.22 (m, 2H), 7.19 (d, 1H, J = 15.6 Hz), 7.12-7.06 (m, 1H), 7.05-6.98 (m, 1H), 6.54 (d, 1H, J = 15.7 Hz), 5.69- .54 (m, 1H), 4.44 (d, 2H, J = 5.9 Hz), 1.60 (s, 6H).
Example 41 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(4-fluoro-benzyl)—N—methyl- isobutyramide :\ /: \/\\\N F l 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), (4-fluoro-benzyl)-methyl-amine (37.4 mg, 0.268 mmol), N—(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1- hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in acetonitrile (1.00 mL) and the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.6 mL of DMSO. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the g solvent to afford 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-(4-fluoro-benzyl)-N—methyl- isobutyramide (24 mg, 22%) as a white lyophilate. MS: 401 (M+H); 1H-NMR (CDCl3, 400 MHz, mixture of rotamers) 5 7.84 (d, 2H, J = 8.6 Hz), 7.46 (d, 2H, J = 8.6 Hz), 7.32-7.13 (m, 3H), 7.06-6.96 (m, 2H), 6.55 (d, 1H, J = 15.7 Hz), .79 (m, 2H), 3.00-2.24 (m, 3H), 1.61 (s, 6H).
Example 42 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-[3-(2-methoxy-ethoxy)-phenyl]- isobutyramide I O\/0 O \S’/ [Q0 V\\\N o N a) 2-Bromoethyl methyl ether (0.800 mL, 8.51 mmol) was added to a mixture of phenol (1.00 g, 7.19 mmol) and ium carbonate (1.49 g, 10.8 mmol) in N- methylpyrrolidinone (6.0 mL) and the mixture was heated at 50 CC in a vial overnight then cooled to room temperature. The mixture was d with water (6 mL) and extracted with 2:1 EtOAc:Hex (3X18 mL). The combined organics were washed with satd. aq.
NaHC03 (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-(2-Methoxy-ethoxy)nitro-benzene (1 .328g, 93%) as an orange oil. b) 1-(2-Methoxy-ethoxy)nitro-benzene (1.32 g, 6.69 mmol) and 10% palladium on carbon (50% Wet) (0.210 g, 0.0987 mmol) in Methanol (15.0 mL) was shaken under an atmosphere of hydrogen (30 psi) for 2h, filtered h Celite and concentrated in vacuo to afford 3-(2-Methoxy-ethoxy)-phenylamine (1.064 g, 95%) as an orange oil. c) 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (85.0 mg, 0.304 mmol), 3-(2-Methoxy-ethoxy)-phenylamine (65 mg, 0.39 mmol), N-(3-dimethylamino- propyl)—N'-ethylcarbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzo- triazole (41.0 mg, 0.303 mmol) were dissolved in itrile (1.5 mL, 29 mmol) and the reaction mixture was allowed to stir at room temperature ght. The reaction was d with 0.4mL DMSO, filtered and purified. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting t afforded 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-[3-(2-methoxy-ethoxy)-phenyl]- isobutyramide (72 mg, 55%) as a white foam. MS: 429 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 7.91 (d, 2H, J = 8.6 Hz), 7.68 (d, 2H, J = 8.6 Hz), 7.23 (d, 1H, J = 15.6 Hz), 7.22 (m, 1H), 7.18 (m, 1H), 6.84 (ddd, 1H, J = 0.6, 1.9, 8.0 Hz), 6.79 (br s, 1H), 6.68 (ddd, 1H, J = 0.6, 2.4, 8.3 Hz), 6.58 (d, 1H, J = 15.6 Hz), 4.11 (m, 2H), 3.73 (m, 2H), 3.44 (s, 3H), 1.70 (s, 6H).
Example 43 (3 - {2- [4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionylamino} -phenoxy)- acetic acid HO o O‘\s”o \EQ 0 V\\\N o N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (85.0 mg, 0.304 mmol), (3-Amino-phenoxy)-acetic acid tert-butyl ester (91 mg, 0.41 mmol, as prepared in Takeda, Y. et al. Chem. Pharm. Bull. 1993, 46, 434), N—(3-dimethylaminopropyl)-N'- arbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole (42 mg, 0.31 mmol) were dissolved in acetonitrile (2.0 mL) and the reaction mixture was allowed to stir at room temperature overnight. The mixture was then treated with trifluoroacetic acid (1.00 mL, 13.0 mmol). After stirring overnight, the mixture was filtered and purified by mass-directed HPLC to afford (3-{2-[4-((E)Cyano- ethenesulfonyl)-phenyl]methyl-propionylamino}-phenoxy)-acetic acid (69 mg, 53%) as a white lyophilate. MS: 429 (M+H); lH-NMR (DMSO-d6, 400 MHz) 8 12.98 (br s, 1H), 9.20 (s, 1H), 8.23 (d, 1H, J = 15.6 Hz), 7.90 (d, 2H, J = 8.6 Hz), 7.67 (d, 2H, J = 8.6 Hz), 7.28 (m, 1H), 7.21 (m, 1H), 7.16 (m, 1H), 6.91 (d, 1H, J = 15.6 Hz), 6.59 (ddd, 1H, J = 1.1, 2.5, 8.0 Hz), 4.61 (s, 2H), 1.59 (s, 6H).
Example 44 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy-benzyl)-isobutyramide O\\ 40 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 3-methoxy-benzylamine (34.7 uL, 0.268 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were ved in acetonitrile (1.00 mL) and the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.6 mL of DMSO. Purification by mass- directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting t afforded 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(3-methoxy- benzyl)-isobutyramide (40 mg, 37%) as a white lyophilate. MS: 399 (M+H); 1H-NMR (CDCl3, 400 MHz) 8 7.85 (d, 2H, J = 8.6 Hz), 7.61 (d, 2H, J = 8.6 Hz), .16 (m, 2H), .78 (m, 1H), 6.77-6.72 (m, 1H), 6.69-6.65 (m, 1H), 6.54 (d, 1H, J = 15.7 Hz), 5.57- .48 (m, 1H), 4.38 (d, 2H, J = 5.7 Hz), 3.77 (s, 3H), 1.64 (s, 6H).
Example 45 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-methoxy-benzyl)-isobutyramide O O \\ // O/ O S\/\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), 2-methoxy-benzylamine (34.7 uL, 0.268 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and 1-hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in acetonitrile (1.00 mL) and the reaction mixture _ 64 _ was allowed to stir for 2 hours at room temperature. The reaction was concentrated under reduced pressure and the residue was taken up in 1.6 mL of DMSO. Purification by mass- ed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent afforded 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-methoxybenzyl )-isobutyramide (48 mg, 45%) as a white lyophilate. MS: 399 (M+H); HNMR (CDCl3, 400 MHz) 8 7.81 (d, 2H, J = 8.7 Hz), 7.53 (d, 2H, J = 8.7 Hz), 7.30-7.23 (m, 1H), 7.23-7.16 (m, 2H), 6.94-6.87 (m, 1H), .80 (m, 1H), 6.54 (d, 1H, J = 15.7 Hz), 5.89- .80 (m, 1H), 4.38 (d, 2H, J = 5.8 Hz), 3.69 (s, 3H), 1.58 (s, 6H).
Example 46 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-methoxy-benzyl)-N-methyl- isobutyramide 0° 00 o/ o S\/\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (75.0 mg, 0.268 mmol), (2-methoxy-benzyl)-methyl-amine (40.6 mg, 0.268 mmol), N—(3- ylaminopropyl)-N'-ethylcarbodiimide hydrochloride (51.5 mg, 0.268 mmol) and l- hydroxybenzotriazole (18.1 mg, 0.134 mmol) were dissolved in acetonitrile (1.00 mL) and the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction was trated under reduced pressure and the e was taken up in 1.6 mL of DMSO. Purification by mass-directed HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent afforded 2-[4-((E)Cyano- ethenesulfonyl)-phenyl]-N-(2-methoxy-benzyl)-N-methyl- isobutyramide (28 mg, 25%) as a white lyophilate. MS: 413 (M+H); 1H-NMR (DMSO-d6, 400 MHz, 100 CC) 8 8.03 (d, 1H, J = 15.7 Hz), 7.87-7.81 (m, 2H), 7.55-7.49 (m, 2H), 7.24-7.17 (m, 1H), 7.02-6.96 (m, 1H), 6.96-6.85 (m, 2H), 6.75 (d, 1H, J = 15.7 Hz), 4.35 (s, 2H), 3.74 (s, 3H), 2.48 (s, 3H), 1.52 (s, 6H) Example 47 (E){4-[1-Methyl(5-phenylamino-[1,3 diazol- 2-yl)-ethyl]-benzenesulfonyl} - acrylonitrile _ 65 _ 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (101 mg, 0.362 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (211 mg, 1.10 mmol) and 4-phenylthiosemicarbazide (65 mg, 0.39 mmol) were combined in methylene chloride (3.00 mL) and stirred overnight. The mixture was concentrated in vacuo, taken up in DMSO and purified by mass-directed HPLC (25-75% ater, TFA modifier). Following lyophilization, (E)—3-{4-[1-Methyl(5-phenylamino- [1,3,4]oxadiazolyl)-ethyl]-benzenesulfonyl}-acrylonitrile trifluoroacetic acid salt (35 mg, 19%) was isolated as an off-white lyophilate. MS: 395 (M+H); 1H-NMR (DMSO- d6, 400 MHz) 8 10.38 (s, 1H), 8.23 (d, 1H, J = 15.6 Hz), 7.91 (d, 2H, J = 8.0 Hz), 7.66 (d, 2H, J = 8.0 Hz), 7.52 (d, 2H, J = 7.8 Hz), 7.32 (m, 2H), 6.98 (m, 1H), 6.92 (d, 1H, J = 15.6 Hz), 1.77 (s, 6H).
Example 48 (E)-3 -{4-[1-(5 amino-[1,3 ,4]oxadiazolyl) methyl-ethyl]-benzenesulfonyl} - acrylonitrile O O \ I \ / /\N/« (E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (105 mg, 0.376 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (241 mg, 1.26 mmol) and 4-ethylthiosemicarbazide (60.0 mg, 0.503 mmol) were combined in methylene chloride (3 mL) and stirred overnight. The mixture was concentrated in vacuo, taken up in DMSO and purified by mass-directed HPLC (25-75% MeCN/water, TFA modifier). Following lyophilization, (E){4-[1-(5-Ethylamino-[1,3,4]oxadiazolyl) methyl-ethyl]-benzenesulfonyl}-acrylonitrile trifluoroacetic acid salt 19 mg, 11%) was isolated as a beige late. MS: 347 (M+H); 1H-NMR (acetone-d6, 400 MHz) 8 7.94 (d, 2H, J = 8.1 Hz), 7.89 (d, 1H, J = 15.7 Hz), 7.66 (d, 2H, J = 8.1 Hz), 6.83 (d, 1H, J = .7 Hz), 6.53 (br s, 1H), 3.30 (q, 2H, J = 7.2 Hz), 1.76 (s, 6H), 1.20 (t, 3H, J = 7.2 Hz).
Example 49 (E){4-[1-(1H-Benzimidazolyl)—1-methyl-ethyl]- esulfonyl} -acrylonitrile Q? \ / s\7\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (112 mg, 0.401 mmol), 1,2-benzenediamine (51.0 mg, 0.472 mmol), N—(3-dimethylaminopropyl)-N'- ethylcarbodiimide hloride (98 mg, 0.51 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) were ed in tetrahydrofuran (6.0 mL) and stirred at room temperature. After 1h, methylene chloride (1.0 mL) was added to aid in solubility. After stirring overnight, Acetic acid (0.65 mL, 11 mmol) was added and the mixture was heated to 70 CC until te ation of the aniline-amide. The mixture was concentrated in vacuo, taken up in DMSO and purified by mass-directed HPLC to afford (E) {4-[1-(1H- Benzimidazolyl)— 1 -methyl-ethyl]-benzenesulfonyl} -acrylonitrile trifluoroacetic acid salt (45 mg, 24%) as an off-white lyophilate. MS: 352 (M+H); 1H-NMR (DMSO-d6, 400 MHz) 5 8.23 (d, 1H, J = 15.7 Hz), 7.90 (d, 2H, J = 8.2 Hz), 7.65 (m, 4H), 7.39 (br s, 2H), 6.91 (d, 1H, J =15.7 Hz), 1.89 (s, 6H).
Example 50 (E){4-[1-Methyl(5-methyl-benzoxazolyl)-ethyl] - benzenesulfonyl} -acrylonitrile 0‘ ,o N A / \ N a) 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (124 mg, 0.444 mmol), 2-aminomethyl-phenol (61.0 mg, 0.495 mmol) and 1-hydroxybenzotriazole (6.0 mg, 0.044 mmol) were combined in 1,2-dichloroethane (4.0 mL, 51 mmol), and N—(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (105 mg, 0.548 mmol) was added. Stir at room temperature in a Vial for 2h, then the mixture was concentrated in vacuo, taken up in DMSO and purified by mass-directed HPLC to afford 2-[4-((E) Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxymethyl-phenyl)- isobutyramide as an oil. b) 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxymethyl-phenyl)- isobutyramide (42 mg, 0.11 mmol) was dissolved in acetic acid (2.0 mL, 35 mmol) and heated at 105 CC for 3d. The e was concentrated in vacuo, taken up in DMSO and purified by mass-directed HPLC (25-85% MeCN:Water, TFA modifier) to afford (E)—3- {4-[1-Methyl(5-methyl-benzoxazolyl)-ethyl]-benzenesulfonyl} -acrylonitrile trifluoroacetic acid salt (15 mg, 28%) as an off-white lyophilate. MS: 367 (M+H); 1H- NMR (DMSO-d6, 400 MHz) 8 8.21 (d, 1H, J = 15.6 Hz), 7.88 (d, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 8.4 Hz), 7.56 (s, 1H), 7.52 (d, 1H, J = 8.3 Hz), 7.18 (d, 1H, J = 8.3 Hz), 6.90 (d, 1H, J = 15.6 Hz), 2.42 (s, 3H), 1.84 (s, 6H).
Example 51 (E){4-[1-Methyl(5-methyl-oxazolyl)-ethyl]- benzenesulfonyl} -acrylonitrile O\\ [/O I"! S\/\\\N 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-propynyl-isobutyramide (53 mg, 0.17 mmol) and gold(III) de (5.0 mg, 0.016 mmol) were combined in acetonitrile-d3 (1.0 mL), and the rate of isomerization was monitored by 1H-NMR. Once complete (4 days) the mixture was filtered and purified by mass-directed HPLC and lyophilized to afford an oil. Reconcentration from MeCN remained an oil, which slowly turned . The mixture was redissolved in MeCN, treated with macroporous carbonate resin (3 mmol/g, 0.1g) for 30 min and filtered to give a clear solution and purple solids which were captured on the filter. Relyophilize as the free base to afford {4-[1-Methyl(5-methyl- oxazolyl)-ethyl]- benzenesulfonyl}-acrylonitrile as an ite wax (16 mg, 30%).
MS: 317 (M+H); 1H-NMR (DMSO-d6, 400 MHz) 8 8.22 (d, 1H, J = 15.6 Hz), 7.86 (d, 2H, J = 8.6 Hz), 7.54 (d, 2H, J = 8.6 Hz), 6.91 (d, 1H, J =15.6 Hz), 6.79 (s, 1H), 2.22 (s, 3H), 1.71 (s, 6H).
Example 52 Cyclohexanecarboxylic acid N'- {2-[4-((E)cyano-ethenesulfonyl)-phenyl]methyl- propionyl} -hydrazide 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (131 mg, 0.469 mmol), cyclohexanecarboxylic acid hydrazide (72.0 mg, 0.506 mmol), N—(3- dimethylaminopropyl)-N'-ethylcarbodiimide hloride (119 mg, 0.621 mmol) and 1- hydroxybenzotriazole (7.0 mg, 0.052 mmol) were combined in itrile (3.0 mL) and stirred at room temperature. After 4h, the mixture was diluted with DMSO (0.4 mL), filtered and purified by mass-directed HPLC (25-85% MeCN:Water, TFA modifier) to afford Cyclohexanecarboxylic acid N'- {2-[4-((E)cyano-ethenesulfonyl)-phenyl] methyl-propionyl}-hydrazide (108 mg, 57%) as a white lyophilate. MS: 404 (M+H); 1H- NMR (DMSO-d6, 400 MHz) 8 9.52 (s, 1H), 9.39 (s, 1H), 8.24 (d, 1H, J = 15.6 Hz), 7.86 (d, 2H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 6.90 (d, 1H, J =15.6 Hz), 2.15 (m, 1H), 1.6- 1.7 (m, 5H), 1.50 (s, 6H), 1.1-1.4 (m, 5H).
Example 53 (E)-3 -{4-[1-(5 hexyl-[1,3 ,4]oxadiazolyl)methyl-ethyl]-benzenesulfonyl}- acrylonitrile exanecarboxylic acid N'- {2-[4-((E)cyano-ethenesulfonyl)-phenyl]methylpropionyl } -hydrazide (52 mg, 0.13 mmol) was dissolved in 1,4-dioxane (2.00 mL) and phosphoryl chloride (0.200 mL, 2.14 mmol) was added and the mixture was heated at 80 0C for 2h, then cooled on ice before being added to 5g of ice. The mixture was diluted with satd. sodium onate (10 mL) and extracted with DCM (3X10 mL). The organic extracts were washed with 1:1 brine:satd. sodium bicarbonate (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford (E)—3- {4-[1-(5-Cyclohexyl- [1,3,4]oxadiazolyl)methyl-ethyl]-benzenesulfonyl}-acrylonitrile (38 mg, 76%) as a white foam. MS: 386 (M+H); HNMR (CDCl3, 400 MHz) 5 7.85 (d, 2H, J = 8.7 Hz), 7.51 (d, 2H, J = 8.7 Hz), 7.20 (d, 1H, J = 15.7 Hz), 6.55 (d, 1H, J = 15.7 Hz), 2.84 (tt, 1H, J = 3.7, 11.3 Hz), 2.03 (m, 2H), 1.84 (s, 6H), 1.79 (m, 2H), 1.71 (m, 2H), 1.24—1.40 (m, 4H).
Example 54 (E)(3 -tert-Butyl-benzenesulfonyl)-acrylonitrile O\\ [/O S\7\\\ To a solution of 3-tert-butyl-bromobenzene (2.13 g, 10 mmol) in anhydrous THF (50 ml) under nitrogen at — 80 CC (ether/dry ice), was added slowly n-BuLi (2.5 M in hexane, 11 mmol). A cloudy suspension was slowly formed. Twenty minutes after BuLi addition, a stream of sulfur dioxide was bubbled through the mixture for 15 min. The on e was then allowed to warm up to room temperature and the solvent was removed under reduced pressure. The sulf1nate residue was ved in water (15 ml), acetic acid (8 ml), and MeOH (20 ml), followed by addition of 2-chloroacrylonitrile (18 mmol). The resulting mixture was stirred at room temperature ght. The organic solvents were removed in vacuo and the residue was diluted with 20 ml of water. The solution was adjusted to pH5-6 with sat. K2HPO4 aq. solution, then extracted with dichloromethane (2x50 ml), dried over MgSO4. After filtration, the filtrate was stirred with triethylamine (20 mmol) for 1 h. The solution was washed with 10% aq. citric acid and brine then dried over MgSO4. The crude product was purified by flash column chromatography (silica gel, dichloromethane/EtOAc, gradient) to give (E)—3-(3-tert-Butyl-benzenesulfonyl)- nitrile (0.76 g, 31%) as a white solid. MS: 250 (M+H); 1H-NMR (CDCl3, 400 MHz) 5 7.89 (s, 1H), 7.76 (d, 1H, J = 7.7 Hz), 7.70 (d, 1H, J = 7.9 Hz), 7.55 (m, 1H), 7.23 (d, 1H, J = 15.9 Hz), 6.55 (d, 1H, J =15.9 Hz), 1.37 (s, 9H). e 55 (E)(4-tert-Butyl-benzenesulfonyl)-acrylamide \\ // s /WCONH2 a) A solution of 4-tert-butyl-bromobenzene (500 mg, 2.34 mmol) in dry THF (10ml) was cooled to -80 oC, treated with phenyl lithium (1.5M, ol) and n-BuLi (1.5M, 2.58 mmol) drop wise at -80 0C. After 30 min, sulfur dioxide gas was bubbled into the mixture for one hour, and then the mixture was allowed to come to room temperature. The reaction mixture was concentrated and washed with diethyl ether to obtain - butylbenzene sulfinic acid lithium salt as a white solid (450 mg, 94%). b) A solution of 4-tert-butylbenzene sulf1nic acid lithium salt (500mg, 2.4mmol) and 2,3- dibromo-propionamide (678 mg, 2.93mmol) in DMF (5 ml) was heated to 80 CC for 15 hours. Then the reaction mixture as diluted with water, ted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (20% Ethyl acetate: Hexane) to obtain (E)(4-tert-Butylbenzenesulfonyl )-acrylamide (50 mg, 8%) as an off white solid, mp = 151 CC. LCMS (ESI): 268 (M+H); 1H-NMR (400MHz, DMSO-d6) 8 1.31 (s, 9H), 6.95-6.98 (d, J: 14.8Hz, 1H), 7.40-7.44 (d, J: 14.8Hz, 1H), 7.69-7.71 (d, J: 8.0Hz, 2H), 7.83-7.85 (d, J = 8.0Hz, 2H), 8.03 (brs, 2H).
Example 56 1-tert-Butyl[((E)-propene)sulfonyl]-benzene O\\ P a) A solution of sodium bicarbonate (1.44g, 17.2mmol) and sodium sulfite (2.16 g, ol) in water (9 ml) was heated to 80 CC for 3h, then 4-tert-butylphenylsulfonyl chloride (2 g, 8.59 mmol) was added in two portions and again heated to 80 0C for 1h. The e was cooled to room temperature, allowed to stand for 2h, and the solids collected by filtration then dried on high vacuum to obtain 4-tert-butylbenzene sulfinic acid sodium salt (1.61 g, 85%) as a white solid. b) Analogous to Example 57b, 1,2-dibromopropane and 4-tert-butylbenzene sulfinic acid sodium salt (0.7 g) afforded 1-tert-Butyl[((E)-propene)sulfonyl]-benzene (130 mg, 17%) as an offwhite solid, mp = 80 °C. LCMS (ESI): 239 (M+H); 1H-NMR (400MHz, CDCl3) 5 1.34 (s, 9H), 1.91-1.93 (dd, J = 6.8, 1.6Hz, 3H), 6.32-6.37 (m, 1H), 6.93-6.99 (m, 1H), 7.53-7.55 (d, J = 8.8Hz, 2H), 7.78-7.80 (d, J = 8.8Hz, 2H).
Example 57 1 -tert-Butyl((E)phenyl-ethenesulfonyl)-benzene A solution of 4-tert-butylbenzene sulfinic acid sodium salt (3.0 g, 13.6 mmol) and 1,2- dibromoethyl e (4.31 g, 16.3 mmol) in DMF (30 ml) was heated to 80 °C for 15h.
The reaction mixture was d by silica gel column chromatography yl acetate: ) to obtain 1-tert-Butyl((E)phenyl-ethenesulfonyl)-benzene (104 mg, 3%) as an off white solid, mp = 95 CC. LCMS (ESI): 301 (M+H); 1H-NMR (400MHz, CDCl3) 5 1.34 (s, 9H), 6.84-6.88 (d, J = 15.6Hz, 1H), 7.38-7.49 (m, 5H), 7.54-7.57 (d, J = 8.4Hz, 2H), 7.65-7.69 (d, J = 15.6Hz, 1H), 7.85-7.88 (d, J = 8.4Hz, 2H).
Example 58 \\ // 1 -tert-Butyl(1 l-ethenesulfonyl)-benzene From the reaction mixture described in Example 59, 1-tert-Butyl(1-phenyl-ethene- sulfonyl)-benzene (147 mg, 4%) was also isolated as an off white solid, mp = 99 oC.
LCMS (ESI): 301 (M+H); 1H-NMR (400MHz, CDCl3) 8 1.29 (s, 9H), 5.93 (s, 1H), 6.59 (s, 1H), 7.28-7.62 (m, 9H).
Example 59 ><©SMOAO o" 'o (E)(4-tert-Butyl-benzenesulfonyl)-acrylic acid ethyl ester A solution of 4-tert-butylbenzene ic acid lithium salt (500 mg, 2.44 mmol) and ethyl 2,3-dibromo propionate (700 mg, 2.69 mmol) in DMF (5ml) was heated to 80 CC for 20h.
The reaction mixture was diluted with water, extracted with ethyl acetate, dried over Na2S04, filtered and concentrated. The crude product was d by silica gel column chromatography (5% Ethyl acetate: ) to obtain (E)(4-tert-Butyl- benzenesulfonyl)-acrylic acid ethyl ester (100 mg, 15%) as an off white solid, mp = 88-91 °C. LCMS (ESI): 297 (M+H); 1H-NMR (400MHz, CDCl3) 8 1.29-1.32 (t, J = 7.2Hz, 3H), 1.35 (s, 9H), 4.22-4.27 (q, J = 7.2Hz, 2H), .83 (d, J = 15.2Hz, 1H), 7.31-7.35 (d, J = 15.2Hz, 1H), 7.58-7.60 (d, J = 8.0Hz, 2H), 7.83-7.85 (d, J = 8.0Hz, 2H).
Example 60 S\¢?A\§§ (E)(4-tert-Butyl-phenylsulfanyl)-acrylonitrile (E)(4-tert-Butyl-benzenesulfonyl)-acrylonitrile (100.0 mg, 0.4011 mmol) was dissolved in Chloroform (2.00 mL) and 4-tert-Butyl-benzenethiol (69 uL, 0.40 mmol) was added, followed by triethylamine (57 uL, 0.41 mmol) and the mixture was stirred at room temperature for 3h, then applied to an ISCO loading cartridge (5g, DCM to transfer).
Chromatography (ISCO 12g, 0-20% EtOAc:Hex) afforded (E)(4-tert-Butyl- phenylsulfanyl)-acrylonitrile (84 mg, 97%) as a clear colorless oil. LCMS (ESI): m/z = 218 (M+H)+; 1H-NMR (CDCl3, 400 MHz) 8 7.3-7.5 (m, 5H), 4.96 (d, 1H, J = 15.6 Hz), 1.34 (s, 9H); 13C-NMR(CDC13, 100 MHz) 8 153.7, 152.7, 133.5, 127.2, 124.8, 117.3, 92.6, 34.9, 31.2.
Example 61 o_ ,0 [2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-acetic acid To a solution of romotert-butylphenoxy)acetic acid (2.86 g, 10 mmol) in anhydrous THF (100 ml) under nitrogen at — 80 oC (ether/dry ice), was added slowly Phenyl lithium in toluene 1.8 M (7 mL, 12.5 mmol). After 5 min, to this mixture, n-BuLi (2.5 M in hexane) (5.2 mL, 13 mmol) was added. A cloudy suspension was slowly formed. Twenty minutes after BuLi addition, a stream of sulfur dioxide was bubbled through the mixture for 15 min. The reaction mixture was then allowed to warm up to room temperature and the solvent was d in vacuo. The sulfinate residue was dissolved in water (15 ml), acetic acid (8 ml), and MeOH (20 ml), followed by addition of roacrylonitrile (1.3 g, 15 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed and the residue was diluted with 20 ml of water. The solution was adjusted to pH5-6 with sat. K2HPO4 aq. solution, then extracted with dichloromethane (2x50 ml) and dried over MgSO4. After filtration, the e was stirred with triethylamine (2.8 mL, 20 mmol) for 1 h. The solution was washed with 10% aq citric acid and brine, and then dried over MgSO4. The final product was d by flash column chromatography (silica gel, romethane/Ethyl acetate, gradient) to give [2-tert-Butyl((E)—2-cyano-ethenesulfonyl)-phenoxy]-acetic acid (1.03 g, 32%) as a white solid. LCMS (ESI): m/z = 322 (M-H)-; 1H-NMR (DMSO-d6, 400 MHz) 13.19 (s, 1H), 8.22 (d, 1H, J = 16.6 Hz), 7.74 (dd, 1H, J = 2.3, 8.7 Hz), 7.68 (d, 1H, J = 2.3 Hz), 7.18 (d, 1H, J = 8.7 Hz), 6.84 (d, 1H, J = 16.6 Hz), 4.90 (s, 2H), 1.40 (s, 9H); 13C-NMR (DMSO-d6, 100 MHz) 5 169.3, 161.4, 149.8, 139.0, 128.6, 128.5, 126.4, 114.7, 113.3, 110.7, 64.9, 34.9, 29.0.
Example 62 O A l l N 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid To a solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1.0 g, 4.15 mmol) in anhydrous THF (50 ml) under nitrogen at — 80 oC (ether/dry ice), was added slowly Phenyl m in toluene 1.8 M (2.77 mL, 4.98 mmol). After 5 min, to this mixture, n- BuLi (2.5 M in ) (2.2 mL, 5.4 mmol) was added. A cloudy suspension was slowly formed. Twenty minutes after BuLi addition, a stream of sulfiar dioxide was bubbled through the mixture for 10 min. The on mixture was then allowed to warm up to room temperature and the solvent was removed in vacuo. The sulf1nate residue was dissolved in water (10 ml), acetic acid (5 ml), and MeOH (15 ml), followed by addition of 2-chloroacrylonitrile (0.54 g, 6.23 mmol). The resulting mixture was stirred at room ature overnight. The organic solvents were removed and the residue was diluted with 20 ml of water. The solution was ed to pH5-6 with sat. K2HPO4 aq. solution, then extracted with dichloromethane (2x30 ml) and dried over MgSO4. After filtration, the filtrate was stirred with triethylamine (1.16 mL, 8.3 mmol) for 1 h. The solution was washed with 10% aq citric acid and brine, then dried over MgSO4. The final product was purified by flash column chromatography (silica gel, dichloromethane/Ethyl acetate, gradient) to give 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid (112 mg, 10%) as a white solid. LCMS (ESI): m/z = 232 (M-CO2H)—; 1H-NMR (DMSO- d6, 400 MHz) 8 12.59 (s, 1H), 8.24 (d, 1H, J = 16.6 Hz), 7.83 (d, 2H, J = 8.5 Hz), 7.66 (d, 2H, J = 8.5 Hz), 6.91 (d, 1H, J = 16.6 Hz), 1.51 (m, 2H), 1.22 (m, 2H).
Example 63 ONTO 2-[2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-N-cyclohexyl-acetamide [2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-acetic acid (57 mg, 0.18 mmol), N—(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hloride (41.0 mg, 0.214 mmol), 1-Hydroxybenzotriazole (5.1 mg, 0.038 mmol) and cyclohexylamine (25 uL, 0.22 mmol) in acetonitrile (0.70 mL) was stirred at room temperature for 5h, then was filtered, rinsing the vial with DMSO (0.3 mL) and the filtrate was purified by mass-directed HPLC (25- 95% MeCNiwater, both containing 0.1% TFA) to afford ert-Butyl((E)cyano- ethenesulfonyl)-phenoxy]-N-cyclohexyl-acetamide (27 mg; 38%) as an off white lyophilate. LCMS (ESI): m/z = 405 (M+H)+; 1H-NMR d6, 400 MHZ) 5 8.22 (d, 1H, J = 15.6 Hz), 7.94 (d, 1H, J = 7.8 Hz), 7.74 (dd, 1H, J = 2.4, 7.8 Hz), 7.67 (d, 1H, J = 2.4 Hz), 4.67 (s, 2H), 3.60 (m, 1H), 1.6-1.8 (m, 4H), 1.55 (m, 1H), 1.38 (s, 9H), 1.1-1.3 (m, 5H).
Example 64 O_ .O F S / N\/\ H O 2-[2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-N-(4-fluoro-benzyl)- acetamide [2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-acetic acid (104 mg, 0.322 mmol), N—(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol), 1- Hydroxybenzotriazole (51 mg, 0.38 mmol) and 4-Fluoro-benzylamine (45 uL, 0.40 mmol) in Acetonitrile (2.0 mL) was stirred at room temperature for 1h, then was added to an ISCO pre-load cartridge (5g) and chromatographed (ISCO 12g, 0-20% Ethyl acetate:Hexanes). Some acetonitrile eluted with product as well as some HOBt. The fraction ning product was concentrated, diluted with MeCN and DCM (3 mL each) and treated with macroporous carbonate resin for 1h. After filtration and concentration, the e was ved in MeCN, diluted with water and then lyophilized to afford 2-[2- tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-N-(4-fluoro-benzyl)-acetamide (64 mg; 46%) as an off-white lyophilate. LCMS (ESI): 431 (M+H); 1H-NMR (DMSO-d6): 5 8.63 (t, 1H, J = 5.9 Hz), 8.23 (d, 1H, J = 15.6 Hz), 7.74 (dd, 1H, J = 2.4, 8.7 Hz), 7.68 (d, 1H, J = 2.4 Hz), 7.32 (m, 2H), 7.1-7.2 (m, 3H), 6.84 (d, 1H, J = 15.6 Hz), 4.79 (s, 2H), 4.33 (d, 2H, J = 5.9 Hz), 1.38 (s, 9H).
Example 65 Come 2-[2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-N-(3-methoxy-phenyl)- acetamide [2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-acetic acid (81 mg, 0.25 mmol), imethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (58.3 mg, 0.304 mmol), 1-Hydroxybenzotriazole (22 mg, 0.16 mmol) and 3-Methoxyaniline (35 uL, 0.31 mmol) in Acetonitrile (1.0 mL) was d at room temperature for 5h, then was filtered, rinsing the vial with DMSO (0.3 mL) and the filtrate was purified by ative HPLC (25-95% MeCNiwater, both containing 0.1% TFA) to afford 2-[2-tert-Butyl((E)cyano- ethenesulfonyl)-phenoxy]-N-(3-methoxy-phenyl)-acetamide (41 mg; 38%) as a white lyophilate. LCMS (ESI): 429 (M+H); 1H-NMR (DMSO-d6): 5 10.26 (s, 1H), 8.22 (d, 1H, J = 15.6 Hz), 7.77 (dd, 1H, J = 2.4, 8.6 Hz), 7.69 (d, 1H, J = 2.4 Hz), 7.30 (m, 1H), 7.23 (m, 1H), 7.17 (d, 1H, J = 8.8 Hz), 7.12 (m, 1H), 6.84 (d, 1H, J =15.6 Hz), 6.67 (dd, 1H, J = 2.5, 8.2 Hz), 4.95 (s, 2H), 3.73 (s, 3H), 1.42 (s, 9H).
Example 66 O S l A (E)-3 - {3 thyl(5 -methyl-benzoxazolyl)—ethyl] -benzenesulfonyl} - acrylonitrile; compound with trifiuoro-acetic acid 1-Hydroxybenzotriazole (40.5 mg, 0.300 mmol), 2-[3-((E)Cyano-ethenesulfonyl)- phenyl]methyl-propionic acid (78.5 mg, 0.281 mmol), 2-Aminomethyl-phenol (38.5 mg, 0.313 mmol) and were combined in acetonitrile (2.0 mL) and stirred in a vial for 6h, then acetic acid (3.0 mL, 53 mmol) was added and the mixture was heated at 90 CC in a sealed vial for 4 days. The mixture was concentrated in vacuo, dissolved in DMSO and purified by preparative mass-directed HPLC (25-75% MeCN:water, both containing 0.1% TFA) to afford (E)—3-{3-[1-Methyl(5-methyl-benzoxazolyl)-ethyl]- esulfonyl}-acrylonitrile; compound with trifiuoro-acetic acid (15 mg; 11%) as purplish-white lyophilate. LCMS (ESI): m/z = 367 (M+H)+; 1H-NMR (CD3CN, 400 MHz) 8 7.84 (m, 1H), 7.79 (m, 1H), 7.73 (m, 1H), 7.61 (m, 1H), 7.52 (m, 1H), 7.51 (d, 1H, J = 15.7 Hz), 7.38 (d, 1H, J = 8.3 Hz), 7.17 (m, 1H), 6.60 (d, 1H, J =15.7 Hz), 2.44 (s, 3H), 1.88 (s, 6H); 13C-NMR (DMSO-d6, 100 MHz) 8 170.3, 148.9, 148.6, 147.2, 140.6, 137.9, 133.9, 132.8, 130.4, 126.8, 126.1, 124.7, 119.6, 114.6, 112.4, 110.2, 41.6, 27.3, .9.
Example 67 _ 77 _ 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid 4- fluoro- benzylamide 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid (51 mg, 0.18 mmol), 4-Fluoro-benzylamine (24.2 uL, 0.213 mmol), N—(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (42.3 mg, 0.221 mmol) and 1-Hydroxybenzotriazole (29 mg, 0.21 mmol) were combined in acetonitrile (1.0 mL) and the reaction mixture was allowed to stir at room temperature for 60 min. The reaction was diluted with 0.5 mL of DMSO, filtered and purified by irected HPLC using a gradient of 25-75% AcN/water both containing 0.1% TFA as the eluting solvent to afford 1-[4-((E)Cyano- ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid o-benzylamide (49 mg; 69%) as a white foam. LCMS (ESI): m/z = 385 (M+H)+; 1H-NMR(DMSO-d6, 400 MHz) 8.23 (d, 1H, J = 15.6 Hz), 7.87 (m, 2H), 7.66 (m, 3H), 7.20 (m, 2H), 7.11 (m, 2H), 6.90 (d, 1H, J = 15.6 Hz), 4.18 (d, 2H, J = 6.0 Hz), 1.42 (dd, 2H, J = 4.2, 7.0 Hz), 1.08 (dd, 2H, J = 4.2, 7.0 Hz). LCMS = 385 (M+H).
Example 68 CLO A 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid cyclohexylamide 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid (37 mg, 0.13 mmol), cyclohexanamine (18 uL, 0.16 mmol), N—(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol) and oxybenzotriazole (23 mg, 0.17 mmol) were combined in acetonitrile (1.0 mL) and the reaction mixture was allowed to stir at room temperature for 60 min. The on was diluted with 0.3 mL of DMSO, filtered and purified by irected HPLC using a gradient of 25-75% MeCN/water both containing 0.1% TFA as the eluting solvent to afford 1-[4-((E) Cyano-ethenesulfonyl)-phenyl]-cyclopropanecarboxylic acid cyclohexylamide (26 mg; 54%) as a white foam. LCMS (ESI): m/z = 359 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8.23 (d, 1H, J = 15.6 Hz), 7.84 (m, 2H), 7.59 (m, 2H), 7.20 (d, 1H, J = 8.1 Hz), 6.90 (d, 1H, J = 15.6 Hz), 3.54 (m, 1H), 1.63 (m, 4H), 1.53 (m, 1H), 1.37 (dd, 2H, J = 4.4, 7.0 Hz), 1.05 (dd, 2H, J = 4.4, 7.0 Hz), 1.02 (m, 1H). LCMS = 359 (M+H).
Example 69 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxymethyl-phenyl)- isobutyramide 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (256 mg, 0.916 mmol), 2-Aminomethyl-phenol (0.133 g, 1.08 mmol), N—(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (221 mg, 1.15 mmol) and 1-Hydroxybenzotriazole (124 mg, 0.916 mmol) were dissolved in acetonitrile (7.0 mL) and the reaction e was allowed to stir at room temperature for 48h. The on was concentrated to ca. 1 mL, then diluted with DMSO and purified by mass-directed HPLC (25-75% MeCN:water, both containing 0.1% TFA). 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxy methyl-phenyl)-isobutyramide (78 mg; 22%) was isolated as beige lyophilate. LCMS (ESI): m/z = 385 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 9.42 (s, 1H), 8.30 (s, 1H), 8.24 (d, 1H, J = 15.7 Hz), 7.91 (d, 2H, J = 8.7 Hz), 7.76 (d, 2H, J = 8.7 Hz), 7.53 (s, 1H), 6.91 (d, 1H, J =15.7 Hz), 6.74 (dd, 1H, J = 2.5, 8.1 Hz), 6.70 (d, 1H, J = 8.1 Hz), 2.17 (s, 3H), 1.62 (s, 6H).
Example 70 O O \ / (E)(2-tert-Butyl-quinolinesulfonyl)-acrylonitrile a) Potassium hydroxide (0.322 g, 5.74 mmol) and Water (1.3 mL) were added to a e of 2-Aminobromo-benzaldehyde (0.933 g, 4.66 mmol) and 3,3-Dimethylbutanone (0.700 mL, 5.60 mmol) at room ature. After 5 min, the mixture was heated at reflux for 3h. The mixture was diluted with water (40 mL) then extracted with DCM (40 mL, 2X20 mL). The c extract was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was d (DCM load onto 24 g loading cartridge, then ISCO 40g, 0-20% Ethyl acetate:hexanes) to afford 6-Bromotert-butylquinoline (0.97 g; 64%) as a yellow oil with small crystals forming. b) To a solution of 6-bromotert-butquuinoline (1 g, 3.8 mmol) in anhydrous THF (50 ml) under nitrogen at — 80 CC (ether/dry ice), was added slowly n-BuLi (2.5 M in hexane) (2 mL, 4.94 mmol). A cloudy suspension was slowly formed. Twenty minutes after BuLi addition, a stream of sulfur dioxide was bubbled through the mixture for 15 min. The reaction mixture was then allowed to warm up to room temperature, the solvent was removed under reduced pressure. The sulflnate residue was dissolved in water (10 ml), acetic acid (5 ml), and MeOH (15 ml), followed by addition of 2-chloroacrylonitrile (0.54 g, 6.23 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed and the e was diluted with 20 ml of water. The solution was ed to pH5-6 with sat. KZHPO4 aq. solution, then extracted with dichloromethane (2x50 ml) and dried over MgSO4. After filtration, the te was d with triethylamine (1.16 mL, 8.3 mmol) for 1 h. The solution was washed with 10% aq citric acid and brine, and then dried over MgSO4. The final t was purified by flash column chromatography (silica gel, romethane/Ethyl acetate, gradient) to give (E)- 3-(2-tert-Butyl-quinolinesulfonyl)-acrylonitrile (0.68 g, 59%) as a white solid. LCMS (ESI): m/z = 301 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.68 (d, 1H, J = 2.1 Hz), 8.61 (d, 1H, J = 8.8 Hz), 8.30 (d, 1H, J = 15.7 Hz), 8.21 (d, 1H, J = 8.9 H), 8.07 (dd, 1H, J = 2.2, 8.9 Hz), 7.92 (d, 1H, J = 8.8 Hz), 6.96 (d, 1H, J = 15.7 Hz), 1.43 (s, 9H).
Example 71 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(3-phenyl-propynyl)-isobutyramide 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (0.254 g, 0.909 mmol), 3-Phenyl-propynylamine hydrochloride (0.272 g, 1.62 mmol), N—(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.225 g, 1.18 mmol) and 1- _ 80 _ Hydroxybenzotriazole (0.019 g, 0.14 mmol) were combined in acetonitrile (6.0 mL). After 1h, 4-Methylmorpholine (0.100 mL, 0.909 mmol) was added, due to only trace conversion to the amide. After 4h, the mixture was concentrated in vacuo to ~1 mL, DMSO was added (1 mL) and the mixture was filtered. Purification of the filtrate by preparative mass- ed HPLC (25-75% MeCNiwater, both containing 0.1% TFA) afforded 2-[4-((E) Cyano-ethenesulfonyl)-phenyl]-N-(3-phenyl-propynyl)-isobutyramide (165 mg; 46%) after partial evaporation in vacuo followed by lyophilization. LCMS (ESI): m/z = 393 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.22 (d, 1H, J = 15.6 Hz), 8.08 (t, 1H, J = 5.5 Hz), 7.86 (d, 2H, J = 8.7 Hz), 7.64 (d, 2H, J = 8.7 Hz), 7.37 (m, 5H), 6.90 (d, 1H, J = 15.6 Hz), 4.08 (d, 2H, J = 5.5 Hz), 1.51 (s, 6H).
Example 72 7‘1 As (E)-3 - {4-[1-Methyl(5 -phenyl-[1,3 ,4]oxadiazolyl)-ethyl]-benzenesulfonyl} - acrylonitrile a) 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (0.262 g, 0.938 mmol), Benzhydrazide (0.160 g, 1.17 mmol), N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (0.232 g, 1.21 mmol) and 1-Hydroxybenzotriazole (0.019 g, 0.14 mmol) were dissolved in acetonitrile (6.0 mL) and the reaction mixture was allowed to stir at room temperature for 4h. The mixture was poured into Ethyl acetate (60 mL), washed with 1N HCl (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Benzoic acid N'- ((E)cyano-ethenesulfonyl)-phenyl] methyl-propionyl}-hydrazide was used in the next step without ation. b) Benzoic acid N'- {2-[4-((E)cyano-ethenesulfonyl)-phenyl]methyl-propionyl} - hydrazide (324 mg, 0.815 mmol) was dissolved in 1,4-Dioxane (12.0 mL) and Phosphoryl chloride (0.500 mL, 5.36 mmol) was added and the e was heated at 90 0C for 2h, then cooled to room temperature and diluted with Ethyl acetate (50 mL). The mixture was washed with satd. NaHCO3 (25 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was ved in DCM and applied to an ISCO cartridge (5g) and purified (ISCO 24g, 0-50% Ethyl acetate:hexanes) to afford a foam after concentration of t containing fractions. This foam was dissolved in MeCN and _ 81 _ water, and then lyophilized to give (E){4-[1-Methyl(5-phenyl-[1,3,4]oxadiazol yl)-ethyl]-benzenesulfonyl}- acrylonitrile as a white solid (223 mg, 72%). LCMS (ESI): m/z = 380 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.22 (d, 1H, J = 15.7 Hz), 7.97 (m, 2H), 7.90 (d, 2H, J = 8.7 Hz), 7.70 (d, 2H, J = 8.7 Hz), 7.55-7.65 (m, 3H), 6.91 (d, 1H, J = .7 Hz), 1.86 (s, 6H); 13C—NMR (DMSO-d6, 100 MHz) 5 170.5, 164.5, 151.6, 149.0, 136.2, 132.0, 129.4, 128.6, 127.5, 126.6, 123.3, 114.5, 112.3, 40.2, 27.1 Example 73 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxy-phenyl)-isobutyramide 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (0.336 g, 1.20 mmol), 2-aminophenol (0.234 g, 2.14 mmol), N—(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.298 g, 1.56 11111101) and 1-Hydroxybenzotriazole (0.162 g, 1.20 mmol) were dissolved in acetonitrile (11.1 mL) and the reaction mixture was allowed to stir at room temperature for 20h. The mixture was poured into Ethyl acetate (200 mL), washed with 1N HCl (25 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The e was applied to an ISCO loading cartridge (24g) as a DCM solution and d on silica gel (ISCO 40g, 5-50% Ethyl acetate:hexanes) to give 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxy-phenyl)-isobutyramide as an off-white solid (213 mg, 48%). LCMS (ESI): m/z = 371 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 9.70 (s, 1H), 8.32 (s, 1H), 8.24 (d, 1H, J = 15.7 Hz), 7.91 (d, 2H, J = 8.6 Hz), 7.77 (d, 2H, J = 8.6 Hz),7.70 (dd, 1H, J = 1.5, 8.0 Hz), 6.88-6.96 (m, 2H), 6.82 (dd, 1H, J = 1.5, 8.0 Hz), 6.75 (dd, 1H, J = 1.2 Hz, 7.5 Hz), 1.62 (s, 6H). e 74 O A l l N (E)Cyano-ethenesulfonyl)- phenyl]-cyclobutanecarboxylic acid To a solution of 1-(4-bromophenyl)cyclobutanecarboxylic acid (5.1 g, 20 mmol) in anhydrous THF (150 ml) under nitrogen at — 80 oC (ether/dry ice), was added slowly Phenyl lithium in toluene 1.8 M (13.9 mL, 25 mmol). After 5 min, to this mixture, n-BuLi (2.5 M in hexane) (10.4 mL, 26 mmol) was added. A cloudy suspension was slowly formed. Twenty s after BuLi on, a stream of sulfiar e was bubbled through the mixture for 15 min. The reaction mixture was then allowed to warm up to room temperature and the solvent was removed in vacuo. The sulf1nate residue was dissolved in water (30 ml), acetic acid (16 ml), and MeOH (40 ml), followed by addition of 2-chloroacrylonitrile (2.6 g, 30 mmol). The resulting mixture was stirred at room ature overnight. The organic solvents were removed and the residue was diluted with 20 ml of water. The solution was adjusted to pH5-6 with sat. K2HPO4 aq. solution, then extracted with dichloromethane (2x100 ml), dried over MgSO4. After tion, the filtrate was stirred with triethylamine (5.6 mL, 40 mmol) for 1 h. The solution was washed with 10% aq citric acid and brine, dried over MgSO4. The final product was purified by flash column tography (silica gel, dichloromethane/Ethyl acetate, gradient) to give 1-[4-((E)Cyano-ethenesulfonyl)- phenyl]-cyclobutanecarboxylic acid (1.52 g, 26%) as a white solid. LCMS (ESI): m/z = 246 (M-CO2H)+; 1H-NMR (DMSO- d6, 400 MHz) 5 12.66 (s, 1H), 8.23 (d, 1H, J = 15.7 Hz), 7.88 (d, 2H, J = 8.5 Hz), 7.58 (d, 2H, J = 8.5 Hz), 6.91 (d, 1H, J = 15.7 Hz), 2.75 (m, 2H), 2.45 (m, 2H), 2.01 (m, 1H), 1.81 (m, 1H);13C-NMR(DMSO-d6, 100 MHz)8175.5, 151.4, 149.1, 135.5, 128.2, 127.8, 114.6, 112.0, 52.0, 31.8, 16.1.
Example 75 GO 8/A 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclobutanecarboxylic acid phenylamide 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclobutanecarboxylic acid (58 mg, 0.20 mmol), 1-Hydroxybenzotriazole (6 mg, 0.04 mmol), N—(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (51 mg, 0.27 mmol) and aniline (21 uL, 0.23 mmol) in acetonitrile (0.5 mL) were d in a vial at room temperature for 1h. The mixture was diluted with DMSO (0.2 mL), d and purified by mass-directed HPLC to afford 1-[4- ((E)Cyano-ethenesulfonyl)-phenyl]-cyclobutanecarboxylic acid phenylamide (34 mg; _ 83 _ 47%). LCMS (ESI): m/z = 367 (M+H)+; 1H-NMR(DMSO-d6, 400 MHz) 8 9.55 (s, 1H), 8.20 (d, 1H, J = 15.6 Hz), 7.91 (d, 2H, J = 8.6 Hz), 7.77 (d, 2H, J = 8.7 Hz), 7.58 (m, 2H), 7.27 (m, 2H), 7.02 (m, 1H), 6.90 (d, 1H, J = 15.6 Hz), 2.90 (M, 2H), 2.53 (m, 2H), 1.86 (m, 2H); 13c—NMR(DMso—d6, 100 MHz) 5 172.6, 151.6, 149.1, 139.0, 135.5, 128.5, 128.3, 127.6, 123.5, 119.9, 114.6, 112.0, 54.1, 32.2, 15.7.
Example 76 1-[4-((E)Cyano-ethenesulfonyl)—phenyl]-cyclobutanecarboxylic acid 4- chloro- benzylamide 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclobutanecarboxylic acid (62 mg, 0.21 mmol) 0.04 mmol), N—(3-Dimethylaminopropyl)—N'- , oxybenzotriazole (6 mg, ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol) and p-Chlorobenzylamine (31 uL, 0.25 mmol) in itrile (1.0 mL) were stirred in a Vial at room temperature for 4h. The mixture was concentrated in vacuo, diluted with DMSO (0.6 mL), filtered and purified by mass-directed HPLC to afford 1-[4-((E)Cyano-ethenesulfonyl)—phenyl]- cyclobutanecarboxylic acid 4-chloro-benzylamide (44 mg; 50%). LCMS (ESI): m/z = 367 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 5 8.37 (t, 1H, J = 6.0 Hz), 8.25 (d, 1H, J = 15.8 Hz), 7.89 (d, 2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.28 (d, 2H, J = 8.5 Hz), 7.06 (d, 2H, J = 8.5 Hz), 6.92 (d, 1H, J = 15.8 Hz), 4.19 (d, 2H, J = 6.0 Hz), 2.78 (M, 2H), 2.43 (m, 2H), 1.84 (m, 2H); 13c—NMR (DMSO-d6, 100 MHz) 5 173.8, 152.2, 149.2, 138.7, 135.4, 131.1, 128.5, 128.13, 128.08, 127.5, 114.6, 112.0, 53.3, 41.7, 32.1, 16.0.
Example 77 00 S/W 1-[4-((E)Cyano-ethenesulfonyl)-phenyl]-cyclobutanecarboxylic acid cyclohexylamide 1-[4-((E)Cyano-ethenesulfony1)—phenyl]-cyclobutanecarboxylic acid (58 mg, 0.20 mmol), 1-Hydroxybenzotriazole (6 mg, 0.04 mmol), N—(3-Dimethylaminopropyl)-N'- _ 84 _ ethylcarbodiimide hydrochloride (51 mg, 0.27 mmol) and cyclohexylamine (26 uL, 0.23 mmol) in acetonitrile (1.0 mL) were stirred in a Vial at room temperature. After 5h, the mixture was poured into Ethyl acetate, washed with 1N HCl, brine, dried over sodium sulfate, filtered and conc. The residue was purified to afford 1-[4-((E)Cyano- ethenesulfonyl)-phenyl]-cyclobutanecarboxylic acid cyclohexylamide (32 mg; 43%).
LCMS (ESI): m/z = 373 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.23 (d, 1H, J = 15.6 Hz), 7.86 (d, 2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.51 (d, 1H, J = 8.0 Hz), 6.90 (d, 1H, J = 15.6 Hz), 3.46 (m, 1H), 2.74 (M, 2H), 2.35 (m, 2H), 1.78 (m, 2H), 1.57 (m, 5H), 1.0-1.2 (m, 5H). e 78 O_ ,O Q?! S /“N (E)-3 -Benzoxazolylmethyl-ethyl)-benzenesulfonyl]-acrylonitrile 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxy-phenyl)-isobutyramide (99 mg, 0.27 mmol) and Methanesulfonic acid (0.50 mL, 7.7 mmol) were heated in 1,4-Dioxane (3.0 mL) in a Vial at 90 CC for 24h. The mixture was cooled to room temperature, partitioned between Ethyl acetate (60 mL) and satd. sodium bicarbonate (60 mL). After separation, the aqueous was extracted with Ethyl acetate (30 mL), then the combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in DCM and applied to an ISCO cartridge (5 g) followed by purification by chromatography (ISCO 40g, 0-40% Ethyl acetate:hexanes) to afford (E)[4-(1-Benzoxazolylmethyl-ethyl)-benzenesulfonyl]- acrylonitrile as a white solid (55% yield). LCMS (ESI): m/z = 353 ; 1H-NMR d6, 400 MHz) 8 8.22 (d, 1H, J = 15.6 Hz), 7.89 (d, 2H, J = 8.7 Hz), 7.78 (m, 1H), 7.66 (m, 3H), 7.38 (m, 2H), 6.90 (d, 1H, J = 15.6 Hz), 1.86 (s, 6H); 13C—NMR (DMSO-d6, 100 70.2, 152.3, 150.4, 149.0, 140.4, 136.0, 128.5, 127.6, 125.2, 124.5, 119.8, 114.6, 112.2, 110.9, 41 .9, 27.3.
Example 79 o_ o N \H/\O 2-[2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-N-(2-hydroxy methyl- phenyl)-acetamide [2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-acetic acid (186 mg, 0.575 mmol), imethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (138 mg, 0.719 mmol), 1-Hydroxybenzotriazole (85.5 mg, 0.633 mmol), and 2-Aminomethyl-phenol (0.142 g, 1.15 mmol) were combined in acetonitrile (6.0 mL) and stirred in a Vial for 3h. The mixture was then added to Ethyl acetate (100 mL) and washed with 1N HC1 (15 mL) and brine (20 mL). The cs were dried over sodium sulfate, diluted with hexane (20 mL) and filtered through 4 mL silica gel (hexane bed), rinsing with 60 mL 1:1 Ethyl acetate:Hexane. The filtrate was concentrated in vacuo, dissolved in DCM and d to an ISCO cartridge (5g) and purified (ISCO 24g, 0-50% Ethyl acetate:hexanes) to afford 2- [2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-N-(2-hydroxymethyl-phenyl)- acetamide (0.195 g; 79%). LCMS (ESI): m/z = 429 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 5 9.80 (s, 1H), 9.18 (s, 1H), 8.23 (d, 1H, J = 15.6 Hz), 7.89 (s, 1H), 7.77 (dd, 1H, J = 2.4, 8.7 Hz), 7.71 (d, 1H, J = 2.4 Hz), 7.25 (d, 1H, J = 8.7 Hz), 6.84 (d, 1H, J =15.6 Hz), 6.75 (m, 2H), 5.00 (s, 2H), 2.19 (s, 3H), 1.44 (s, 9H); R (DMSO-d6, 100 MHz) 5 165.2,161.3,149.7,144.5,139.0,128.8,128.7,127.6,126.5,125.5,124.7,121.1,114.7, 114.7, 113.7, 110.8 20.5. , 67.5, 34.9, 29.2, Example 80 \\ o ,o N—Butynyl[4-((E)cyano-ethenesulfonyl)-phenyl]-isobutyramide 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid (0.254 g, 0.909 mmol), Butynamine hydrochloride (0.171 g, 1.62 mmol), N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.225 g, 1.18 mol), 4- Methylmorpholine (0.100 mL, 0.909 mmol) and 1-Hydroxybenzotriazole (0.019 g, 0.14 mmol) were combined in Acetonitrile (6.0 mL). After 45m, the mixture was concentrated in vacuo to ~1 mL, DMSO was added (1 mL) and the mixture was filtered. Purification of the filtrate by mass-directed HPLC (25-75% MeCN:water, 0.1% TFA) ed N—But ynyl[4-((E)cyano-ethenesulfonyl)-phenyl]-isobutyramide (48 mg, 16%). LCMS (ESI): m/z = 331 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.23 (d, 1H, J = 15.7 Hz), 7.85 (d, 2H, J = 8.7 Hz), 7.66 (t, 1H, J = 5.7 Hz), 7.62 (d, 2H, J = 8.7 Hz), 6.90 (d, 1H, J = .7 Hz), 3.16 (m, 2H), 2.79 (t, 1H, J = 2.7 Hz), 2.28 (dt, 2H, J = 2.7, 7.1 Hz), 1.47 (s, 6H).
Example 81 Njflo (E)[3-tert-Butyl(5-methyl-benzoxazolylmethoxy)-benzenesulfonyl]- acrylonitrile 2-[2-tert-Butyl((E)cyano-ethenesulfonyl)-phenoxy]-N-(2-hydroxy-5 -methylphenyl amide (0.178 g, 0.415 mmol) was heated in 1,4-Dioxane (6.0 mL) with methanesulfonic acid (1.0 mL, 15 mmol) at 90 0C for 8h. The mixture was cooled to room temperature, stirred for 48 h, then was treated with additional methanesulfonic acid (1 mL) and heated for 3h at 90 CC. The mixture was cooled and added into Ethyl acetate (80 mL) and satd. NaHCO3 (40 mL). The layers were separated and the organics washed with brine (20 mL), dried over sodium sulfate, d and concentrated in vacuo. The residue was dissolved in DCM, applied to an ISCO dge (5g) and purified (ISCO 40g, 0-40% Ethyl acetate:hexanes) to afford [3-tert-Butyl(5-methyl-benzoxazol ylmethoxy)-benzenesulfonyl]-acrylonitrile (86 mg; 50%). LCMS (ESI): m/z = 411 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.23 (d, 1H, J = 15.7 Hz), 7.80 (dd, 1H, J = 2.4, 8.7 Hz), 7.72 (d, 1H, J = 2.4 Hz), 7.64 (d, 1H, J = 8.4 Hz), 7.61 (m, 1H), 7.46 (d, 1H, J = 8.7 Hz), 7.26 (dd, 1H, J = 1.2, 8.4 Hz), 6.85 (d, 1H, J = 15.7 Hz), 5.67 (s, 2H), 2.43 (s, 3H), 1.39 (s, 9H).
Example 82 4-[4-((E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid To a solution of 1-(4-bromophenyl)tetrahydro-2H-pyrancarboxylic acid (2.85 g, 10 mmol) in ous THF (100 ml) under en at — 80 oC (ether/dry ice), was added slowly Phenyl lithium in toluene 1.8 M (7 mL, 12.5 mmol). After 5 min, to this mixture, n- BuLi (2.5 M in hexane) (5.2 mL, 13 mmol) was added. A cloudy sion was slowly formed. Twenty minutes after BuLi addition, a stream of sulfur dioxide was bubbled through the mixture for 15 min. The reaction mixture was then allowed to warm up to room temperature and the t was removed in vacuo. The ate residue was dissolved in water (15 ml), acetic acid (8 ml), and MeOH (20 ml), followed by addition of 2-chloroacrylonitrile (1.3 g, 15 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed and the residue was diluted with 20 ml of water. The solution was ed to pH5-6 with sat. K2HPO4 aq. solution, then extracted with dichloromethane (2x50 ml), dried over MgSO4. After filtration, the filtrate was stirred with triethylamine (2.8 mL, 20 mmol) for 1 h. The solution was washed with 10% aq citric acid and brine, dried over MgSO4. The final product was purified by flash column chromatography (silica gel, dichloromethane/Ethyl acetate, gradient) to give 4-[4-((E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyran carboxylic acid (0.87 g, 27%) as a white solid. LCMS (ESI): m/z = 276 (M-CO2H)+; 1H- NMR (DMSO-d6, 400 MHz) 8 13.00 (s, 1H), 8.23 (d, 1H, J = 15.7 Hz), 7.91 (d, 2H, J = 8.7 Hz), 7.74 (d, 2H, J = 8.7 Hz), 6.92 (d, 1H, J = 15.7 Hz), 3.82 (m, 2H), 3.48 (m, 2H), 2.40 (m, 2H), 1.88 (m, 2H); 13c—NMR (DMSO-d6, 100 MHz) 5 174.3, 150.2, 149.0, 136.1, 128.4, 127.6, 114.6, 112.2, 64.6, 48.5, 33.7.
Example 83 4-[4-((E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyran—4-carboxylic acid cyclohexylamide 4-[4-((E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid (61 mg, 0.19 mmol), cyclohexylamine (33 uL, 0.29 mmol), 1-Hydroxybenzotriazole (25.6 mg, 0.190 mmol) and N—(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol) were combined in itrile (6.0 mL) and stirred at room ature.
After 4h, the mixture was trated in vacuo, dissolved in DMSO and purified by mass-directed HPLC (25-75% ater, 0.1% TFA ) to give 4-[4-((E)Cyano- ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid cyclohexylamide (39 mg, 51%). LCMS (ESI): m/z = 403 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.23 (d, 1H, J = 15.6 Hz), 7.87 (d, 2H, J = 8.6 Hz), 7.66 (d, 2H, J = 8.6 Hz), 7.45 (d, 1H, 8.0 Hz), 6.91 (d, 1H, J = 15.7 Hz), 3.77 (m, 2H), 3.56 (m, 1H), 3.44 (m, 2H), 1.83 (m, 2H), 1.62 (m, 6H), 1.12 (m, 6H).
Example 84 4-[4-((E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyran—4-carboxylic acid phenylamide 4-[4-((E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid (67 mg, 0.21 mmol), aniline (29 uL, 0.32 mmol), 1-Hydroxybenzotriazole (7.0 mg, 0.052 mmol) and N—(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (50.0 mg, 0.261 mmol) were combined in acetonitrile (3.00 mL) and stirred at room temperature. After 24h, the mixture was concentrated in vacuo, dissolved in DMSO and purified by mass- directed HPLC (25-75% MeCN:water, 0.1% TFA ) to give 4-[4-((E)Cyano- ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid phenylamide (23 mg, 28%).
LCMS (ESI): m/z = 397 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 5 9.38 (s, 1H), 8.22 (d, 1H, J = 15.7 Hz), 7.93 (d, 2H, J = 8.7 Hz), 7.76 (d, 2H, J = 8.7 Hz), 7.54 (m, 2H), 7.28 (m, 2H), 7.06 (m, 1H), 6.91 (d, 1H, J = 15.7 Hz), 3.81 (m, 2H), 3.55 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H).
Example 85 4-[4-((E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid ro- benzylamide (E)Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid (72 mg, 0.22 mmol), p-Chlorobenzylamine (45 uL, 0.37 mmol), 1-Hydroxybenzotriazole (9.0 mg, 0.067 mmol) and N—(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol) were combined in acetonitrile (6.0 mL, 110 mmol) and stirred at room temperature. After 2h, the e was concentrated in vacuo, dissolved in DMSO and purified by mass-directed HPLC (25-75% MeCN:water, 0.1% TFA ) to give 4-[4-((E) Cyano-ethenesulfonyl)-phenyl]-tetrahydro-pyrancarboxylic acid 4-chloro-benzylamide (32 mg 32%). LCMS (ESI): m/z = 445 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) 8 8.36 (t, 1H, J = 5.9 Hz), 8.26 (d, 1H, J = 15.6 Hz), 7.90 (d, 2H, J = 8.6 Hz), 7.69 (d, 2H, J = 8.6 Hz), 7.27 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.93 (d, 1H, J = 15.6 Hz), 4.21 (d, 2H, J = 5.9 Hz), 3.76 (m, 2H), 3.46 (m, 2H), 2.52 (m, 2H), 1.90 (m, 2H).
Example 86 l \N N N 2-[5-((E)Cyano-ethenesulfonyl)-pyridinyl]-N-cyclohexyl-isobutyramide a) To a suspension of 2-(5-bromopyridinyl)methylpropanoic acid (1.22 g, 5 mmol) in 25 mL ofDMF was added TEA (2.1 mL, 15 mmol) and cyclohexylamine (0.86 mL, 7.5 mmol) and followed by propylphosphonic anhydride (50% solution in DMF) (8.9 mL, mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 2h. The mixture was concentrated in vacuo, dissolved in DCM (100mL) and brine (50 mL), separated and the organic phase was concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, dichloromethane/Acetone, gradient) to give 2-(5-Bromo-pyridinyl)-N-cyclohexyl- isobutyramide (0.83 g, 5 l%) as a white solid. b) To a solution of 2-(5-Bromo-pyridinyl)-N-cyclohexyl-isobutyramide (0.8 g, 3.3 mmol) in anhydrous THF (100 ml) under nitrogen at — 80 oC (ether/dry ice), was added slowly Phenyl lithium in toluene 1.8 M (2.3 mL, 4.1 mmol). After 5 min, to this mixture, n-BuLi (2.5 M in hexane) (l .7 mL, 4.3 mmol) was added. A cloudy suspension was slowly . Twenty minutes after BuLi addition, a stream of sulfur dioxide was bubbled through the mixture for 10 min. The on mixture was then d to warm up to room temperature and the solvent was removed in vacuo. The sulfinate residue was dissolved in water (10 ml), acetic acid (5 ml), and MeOH (15 ml), followed by addition of 2-chloroacrylonitrile (0.43 g, 5.0 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed and the residue was d with 20 ml of water. The solution was adjusted to pH5-6 with sat. K2HPO4 aq. solution, then extracted with dichloromethane (2x30 ml) and dried over MgSO4. After filtration, the filtrate was stirred with triethylamine (0.92 mL, 6.6 mmol) for l h. The solution was washed with 10% aq citric acid and brine, then dried over MgSO4. The final product was purified by flash column chromatography (silica gel, dichloromethane/Ethyl acetate, gradient) to give 2-[5-((E)Cyano-ethenesulfonyl)-pyridinyl]-N-cyclohexyl- isobutyramide (182 mg, 15%) as a white solid. LCMS (ESI): m/z = 362 (M+H)+; 1H- NMR (DMSO-d6, 400 MHz) 8 8.97 (dd, 1H, J = 0.6, 2.4 Hz), 8.28 (d, 1H, J = 15.7 Hz), 8.24 (dd, 1H, J = 2.4, 8.5 Hz), 7.62 (dd, 1H, J = 0.6, 8.5 Hz), 7.22 (d, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 15.7 Hz), 3.55 (m, 1H), 1.66 (m, 4H), 1.53 (m, 1H), 1.49 (s, 6H), 1.0-1.2 (m, 5H).
Cell Cultures and Transfection. BxPc-3 and Su.86.86 atic and HT-29 colon and A2780 ovarian cancer cell lines were sed from ATCC and cultured in DMEM supplemented with 10% fetal bovine serum, ine, penicillin, and streptomycin. All cells were cultured at 37 CC in a humidified incubator in a 5% C02 atmosphere. The cancer cell lines were transduced with a retrovirus containing pLuc- _ 91 _ puro, a constitutive luciferase reporter and selected in G418-containing media. Transient transfection of a full-length human c-FLIP uct in the vector pcDNA3 was performed as previously described. Scaife et al. Cancer Research 2002, 62: 6870-78.
Cell survival and adhesion assay. Pancreatic cancer cell cultures (BxPc-3 and Su.86.86) and colon cancer ) and ovarian cancer (A2780)cells that were stably transfected with a firefly luciferase construct were transiently ded with trypsin-PBS. 105 cells were overlayed onto confluent monolayers of human mesothelial cells in 96-well plates while simultaneously adding various concentrations of compounds of the invention or DMSO for 5 hours. The non-adherent cells were carefully washed away from the wells twice with 100ul/well of blocking buffer (1% BSA in PBS) and twice again with ice-cold PBS. nt and surviving cells were detected by luciferase activity in a luminometer as follows. The cells were lysed in 0.1% TritonX-lOO, 25 mM Gly-Gly (7.8), MgSO4, 4 mM EGTA, lmM DTT. The total n tration was normalized with lysis buffer. 50 ul of cell lysate was added per well of a 96-well iter plate. 50ul of luciferin substrate (Promega) was added per well and then the light output determined in a luminometer. Results for compounds of the present invention at a tration of 10 uM are shown in Table I.
Athymic Mouse Cancer Studies. The animal studies were approved by and performed in accordance with the University of Utah and University of Hawaii Institutional Animal Care and Use Committee. Athymic 5-week-old female nu/nu mice were randomized to intraperitoneal (IP) treatment with either compounds of the invention (5 mg/kg) or an equal volume of vehicle (DMSO) 4 hours prior to IP injection of 106 suspended Su.86.86, BxPc-3, or HT-29 cells, or FLIP —high (CD133+). The mice continued to receive DMSO or compounds of the invention (5 mg/kg) IP every 3 days for 8-9 days. A mixture of 10 ul/gm of firefly D-luciferin (15 mg/ml stock) (Xenogen), 200 ul (stock = 100 mg/ml) ketamine HCl, and 20 ul xylazine (stock = ml) in pH 7.4 PBS was injected IP just prior to bioluminescent imaging in order to anesthetize the mice and provide substrate for the rase expressing cancer cells. The mice were euthanized and the nal cavity exposed surgically. The peritoneal tumor implants were imaged with the Xenogen bioluminescent imaging . The tumor implants for each mouse were verified with a dissecting zoom microscope and histopathology.
References Burns, T. F., and El-Deiry, W. S. (2001). Identification of inhibitors of TRAIL- induced death (1T1Ds) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach. J Biol Chem 276, 37879-37886.
De Vita, V. T., Hellman, S., and Rosenberg, S. A. (2001). Cancer: Principles and Practice of gy, 5 edn (Philadelphia: cott Williams and Wilkins).
Elnemr, A., Ohta, T., , A., ra, M., Kitagawa, H., Fujimura, T., ya, 1., Fushida, S., Nishimura, G. 1., Shimizu, K., and Miwa, K. (2001). Human pancreatic cancer cells disable function of Fas receptors at several levels in Pas signal transduction pathway. Int J Oncol I 8, 311-316.
Fujiwara, K. (2000). Intraperitoneal herapy and intraperitoneal washing cytology in management of ovarian cancer. Gan To Kagaku Ryoho 2 7 Suppl 2, 8.
Johnstone, P. A., and Sindelar, W. F. (1993). ns of disease recurrence following definitive therapy of adenocarcinoma of the pancreas using surgery and adjuvant radiotherapy:correlations of a clinical trial. Int J Radiat Oncol Biol Phys 2 7, 831- 834.
Kanellos, 1., Demetriades, H., Zintzaras, E., Mandrali, A., Mantzoros, 1., and Betsis, D. (2003). Incidence and prognostic value of positive neal cytology in colorectal cancer. Dis Colon Rectum 46, 535-539.
Nakatsuka, A., Yamaguchi, K., Shimizu, S., Yokohata, K., Morisaki, T., Chijiiwa, K., and Tanaka, M. (1999). Positive washing cytology in ts with pancreatic cancer indicates a contraindication of pancreatectomy. Int J Surg 1nvestig I 311-317.
Santala, M., Talvensaari-Mattila, A., and Kauppila, A. (2003). Peritoneal cytology and preoperative serum CA 125 level are important prognostic indicators of overall survival in advanced trial cancer. Anticancer Res 23, 3097-3103.
Terauchi, F., Moritake, T., Yamamoto, Y., and Ogura, H. (2002). Combination chemotherapy with paclitaxel and intraperitoneal cisplatin for ovarian cancer with disseminated s in the peritoneum and the diaphragm. Int J Clin Oncol 7, 356-360.
Yachida, S., Fukushima, N., to, M., Matsuno, Y., Kosuge, T., and Hirohashi, S. (2002). Implications of peritoneal washing cytology in patients with potentially resectable atic cancer. Br J Surg 89, 573-578.
Yu, W., Whang, 1., Suh, 1., Averbach, A., Chang, D., and aker, P. H. (1998).
Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer. Ann Surg 228, 347-354. _ 93 _ Zhang, L., and Fang, B. (2005). isms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther [2, 228-237.
THE

Claims (45)

CLAIMS 1. NG THE ION ARE AS FOLLOWS:
1. A compound of formula I, or a pharmaceutically acceptable salt form f, wherein A is at the 3 - or 4 - position of the phenyl ring; and A is or ; R1 and R 2 are each ndently substitute d or unsubstituted alkyl or R 1 and R 2, together with the carbon atom to which they are attached, form a three - to seven - membered substituted or unsubstituted cycloalkyl ring; R3 is -OH, tuted or unsubstituted alkyl, substituted or unsubstituted cycl oalkyl, substituted or unsubstituted cycloalkalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, tuted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalky lalkyl, or –NR 4R5; R4 and R 5 are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyene oxide, tuted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, -COOalkyl, -COalkyl, -COcycloalkyl, -NHCOalkyl, -NHCOaryl, or - NHCOcycloalkyl; or R 4 and R 5, together with the atoms through which they are ed, form a substituted or unsubstituted heterocycloalkyl ring; and R6 is substituted or unsubstituted heteroaryl.
2. The compound of claim 1, wherein A is at the 4 -position of the phenyl ring.
3. The compound of claim 1, wherein A is .
4. The compound of claim 3, wherein R 1 and R 2 are each -CH 3.
5. The compound of claim 3, wherein R 3 is -OH.
6. The compound of claim 3, wherein R 3 is tuted or unsubstituted heterocycloalkyl.
7. The compound of claim 3, wherein R 3 is -NR 4R5.
8. The compound of claim 7, wherein R 4 and R 5, together with the atoms through which they are attached, form a substituted or unsubstituted heterocycloalkyl ring.
9. The compound of claim 7, wherein R 4 is H.
10. The nd of claim 9, wherein R 5 is substitute d or unsubstituted alkyl.
11. The compound of claim 9, wherein R 5 is substituted or unsubstituted aryl.
12. The compound of claim 9, wherein R 5 is substituted or unsubstituted aralkyl.
13. The compound of claim 9, wherein R 5 is substituted or unsubstitu ted heteroaryl.
14. The nd of claim 9, wherein R 5 is substituted or unsubstituted aralkyl.
15. The compound of claim 9, n R 5 is substituted or unsubstituted cycloalkyl.
16. The compound of claim 9, wherein R 5 is substituted or unsubst ituted heterocycloalkyl.
17. The compound of claim 9, wherein R 5 is substituted or unsubstituted e oxide.
18. The compound of claim 9, wherein R 5 is -NHCOcycloalkyl.
19. The nd of claim 3, wherein R 4 is -CH 3.
20. The compound of claim 19, w herein R 5 is substituted or unsubstituted alkyl.
21. The compound of claim 19, wherein R 5 is substituted or unsubstituted aryl.
22. The compound of claim 19, n R 5 is substituted or unsubstituted aralkyl.
23. The compound of claim 19, wherein R 5 is substituted or unsubstituted heteroaryl.
24. The compound of claim 19, wherein R 5 is substituted or unsubstituted heteroaralkyl.
25. The compound of claim 19, wherein R 5 is substituted or unsubstituted cycloalkyl.
26. The nd of claim 19, wherein R5 is substituted or unsubstituted heterocycloalkyl.
27. The compound of claim 19, n R5 is substituted or unsubstituted alkyene oxide.
28. The compound of claim 19, wherein R5 is -NHCOcycloalkyl.
29. The compound of claim 1, wherein A is .
30. The compound of claim 29, wherein R1 and R2 are each -CH3.
31. The compound of claim 29, wherein R6 is substituted or unsubstituted oxadiazolyl.
32. The compound of claim 29, wherein R6 is substituted or unsubstituted benzoimidazolyl.
33. The nd of claim 29, wherein R6 is tuted or unsubstituted benzooxazolyl.
34. The compound of claim 29, wherein R6 is substituted or unsubstituted yl.
35. The compound of claim 1, wherein the compound: 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid; 2-[3-((E)Cyano-ethenesulfonyl)-phenyl]methyl-propionic acid; (E)[4-(l , 1 -Dimethylmorpholinyloxo-ethyl)-benzenesulfonyl]- acrylonitrile; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2-hydroxy-ethyl)-isobutyramide; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-phenyl-isobutyramide; N-Benzyl[4-((E)cyano-ethenesulfonyl)-phenyl]-isobutyramide; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-pyridinylmethyl-isobutyramide; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-isobutyl-isobutyramide; (E) {4-[ 1 , 1 -Dimethyl(4-methyl-piperazin- 1-yl)- 2-oxo-ethyl]-benzenesulfonyl} - acrylonitrile; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-cyclopropylmethyl-isobutyramide; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(2,2-difluoro-ethyl)-isobutyramide; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-cyclohexyl-isobutyramide; 2-[4-((E)Cyano-ethenesulfonyl)-phenyl]-N-(tetrahydro-pyranyl)-isobutyramide; N-(4 -Chloro l) [4 -((E) cyano -ethenesulfonyl) -phenyl] -isobutyram ide; 2-[4 -((E) Cyano esulfonyl) -phenyl] -N-thiophen ylmethyl tyramide; 2-[4 -((E) no -ethenesulfonyl) -phenyl] -N-((S) -l-phenyl -ethyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-((R) phenyl -ethyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -fluoro -benzyl) -isobutyramide; (E) -3 - {4 -[2 -(3 ,4 -Dihydro - 1 H inolin yl) - 1 , 1 -dimethyl oxo -ethyl] - benzenesulfonyl} -acrylonitrile; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -pyrazol -l-yl -benzyl) -isobutyramide; N-Benzyl [4 -((E) cyano -ethenesulfonyl) -phenyl] -N-methyl -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -methoxy -phenyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] nethyl -isobutyramide; 2- [4 -((E) Cy ano -ethenesulfonyl) -phenyl] -N-(3 -methoxy l) -isobutyramide; 2-[4 -((E) no esulfonyl) -phenyl] -N-(4 -sulfamoyl l) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -methanesulfonyl -benzyl) -isobutyramide; (E) [4 -(l , 1 -Dime thyl oxo piperidin yl -ethyl) -benzenesulfonyl] -acrylonitrile; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-((S) hydroxy -l-phenyl -ethyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-((S) oxo -azepan yl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-[4 -(2 -methoxy -ethoxymethyl) -phenyl] - isobutyramide; (2 -{2 -[4 -((E) Cyano -ethenesulfonyl) -phenyl] hyl -propionylamino} -ethyl) -carbamic acid tert -butyl ester; (6 -{2 -[4 -((E) Cyano -ethenesulfonyl) -phenyl] methyl -prop ionylamino} ) -carbamic acid tert -butyl ester; {2 -[2 -(2 - {2 -[4 -((E) Cyano -ethenesulfonyl) -phenyl] - 2-methyl -propionylamino} -ethoxy) - ethoxy] -ethyl} -carbamic acid tert -butyl ester; 2-[3 -((E) no -ethenesulfonyl) -phenyl] -N-cyclohexyl -isobutyramide ; 2-[3 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(3 -methoxy -phenyl) -isobutyramide; 2-[3 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -fluoro -benzyl) -isobutyramide; N-(4 -Amino -benzyl) [4 -((E) cyano -ethenesulfonyl) l] tyramide; 2-[4 -((E) Cyano -ethe nesulfonyl) -phenyl] -N-(3 -fluoro -benzyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(2 -fluoro -benzyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 o -benzyl) hyl -isobutyramide; 2-[4 -((E) Cyano esulfonyl) -phe nyl] -N-[3 -(2 -methoxy -ethoxy) -phenyl] - isobutyramide; (3 -{2 -[4 -((E) Cyano -ethenesulfonyl) -phenyl] hyl -propionylamino} -phenoxy) -acetic acid; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(3 -methoxy -benzyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfony l) -phenyl] -N-(2 -methoxy -benzyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(2 xy -benzyl) -N-methyl -isobutyramide; (E) {4 -[ 1 l (5 -phenylamino -[ 1 ,3,4]oxadiazol - 2-yl) -ethyl] -benzenesulfonyl} - nitrile; (E) {4 -[l -(5 -Ethylamino -[ 1 ,3,4]oxadiazol yl) methyl -ethyl] -benzenesulfonyl} - acrylonitrile; (E) {4 -[ 1 -( 1 H -Benzimidazol yl) methyl -ethyl] - benzenesulfonyl} onitrile; (E) {4 -[ 1 -Methyl -1 -(5 -methyl -benzoxazol yl) -ethyl] - benzenesu lfonyl} -acrylonitrile; (E) {4 -[ 1 -Methyl -1 -(5 -methyl -oxazol yl) -ethyl] - benzenesulfonyl} -acrylonitrile; Cyclohexanecarboxylic acid N' - {2 -[4 -((E) cyano -ethenesulfonyl) -phenyl] methyl - propionyl} -hydrazide; or (E) {4 -[l -(5 hexyl -[l,3, 4]oxadiazol yl) -l-methyl -ethyl] -benzenesulfonyl} - acrylonitrile; or a pharmaceutically acceptable salt form thereof.
36. A pharmaceutical composition comprising a compound ing to any one of claims 1 to 35, or a pharmaceutically acceptable salt for m thereof, and a pharmaceutically able carrier or diluent.
37. The use of the composition of claim 36 for the cture of a medicament for treating or reducing the risk of peritoneal carcinomatosis in a patient that has had an intra -abdominal can cer removed.
38. The use of a compound according to any one of claims 1 to 35 for the manufacture of a medicament for treating or reducing the risk of peritoneal carcinomatosis in a patient that has had an intra -abdominal cancer removed.
39. The use acco rding to claim 37 or 38, n the intra -abdominal cancer is located at or near the colon, at or near the ovary, at or near the rectum, at or near the stomach, or at or near the pancreas of the patient.
40. A compound of formula I, or a pharmaceutically acceptable salt form thereof, O O 1 S 3 CN A I wherein A is at the 3 - or 4 - position of the phenyl ring; and A is R2 R1 ; R1 and R 2 are each are each –CH 3; R3 is –NR 4R5; R4 is H; and R5 are each independe ntly H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyene oxide, substituted or tituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted l, substit uted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, -NHCOcycloalkyl; or R 4 and R 5, together with the atoms through which they are attached, form a substituted or unsubstituted heterocycloalkyl ring.
41. A compound of a I, o r a pharmaceutically acceptable salt form thereof, O O 1 S 3 CN A I n A is at the 3 - or 4 - position of the phenyl ring; and A is R2 R1 ; R1 and R 2 are each –CH 3; and R6 is substituted or unsubstituted aryl.
42. A compound which is: 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-phenyl -isobutyramide; N-Benzyl [4 -((E) cyano -ethenesulfonyl) -phenyl] -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-isobutyl -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) l] -N-cyclopropylmethyl -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] lohexyl -isobutyramide; N-(4 -Chloro -benzyl) [4 -((E) cyano -ethenesulfonyl) -phenyl] -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-thiop hen ylmethyl -isobutyramide; 2-[4 -((E) no -ethenesulfonyl) l] -N-((S) phenyl -ethyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) l] -N-((R) phenyl -ethyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -fluoro l) -iso butyramide; (E) {4 -[2 -(3,4 -Dihydro -1H -isoquinolin yl) -1,1 -dimethyl oxo -ethyl] -benzenesulfonyl} - acrylonitrile; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 ol yl -benzyl) -isobutyramide; N-Benzyl [4 -((E) cyano -ethenesulfonyl) -phenyl] -N-meth yl -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -methoxy -phenyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-phenethyl -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(3 -methoxy -phenyl) -isobutyramide; (E) [4 -(1,1 -Dimethyl oxo piperidin yl -ethyl) -benzenesulfonyl] -acrylonitrile; 2-[4 -((E) Cyano -ethenesulfonyl) l] -N-((S) hydroxy phenyl -ethyl) - isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) l] -N-((S) oxo -azepan yl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-[4 -(2 -methoxy -ethoxymethyl) -phenyl] - isobutyramide; (2 -{2 -[4 -((E) Cyano -ethenesulfonyl) -phenyl] hyl -propionylamino} -ethyl) -carbamic acid tert -butyl ester; (6 -{2 -[4 -((E) Cyano -ethenesulfonyl) -phenyl] methyl -propion ylamino} -hexyl) -carbamic acid tert -butyl ester; 2-[3 -((E) no -ethenesulfonyl) -phenyl] lohexyl -isobutyramide; 2-[3 -((E) no -ethenesulfonyl) -phenyl] -N-(3 -methoxy -phenyl) -isobutyramide; 2-[3 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 o -benzyl )-isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) l] -N-(3 -fluoro -benzyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(2 -fluoro -benzyl) -isobutyramide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(4 -fluoro -benzyl) -N-methyl - isobutyramide ; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-[3 -(2 -methoxy -ethoxy) -phenyl] - isobutyramide; (3 -{2 -[4 -((E) Cyano -ethenesulfonyl) -phenyl] methyl -propionylamino} -phenoxy) -acetic acid; 2-[4 -((E) Cyano esulfonyl) -phenyl] -N-(3 -methoxy -benzyl) -isobutyra mide; 2-[4 -((E) Cyano -ethenesulfonyl) -phenyl] -N-(2 -methoxy -benzyl) -isobutyramide; 2-[4 -((E) no -ethenesulfonyl) -phenyl] -N-(2 -methoxy l) -N-methyl - isobutyramide; (E) {4 -[1 -Methyl (5 -phenylamino -[1,3,4]oxadiazol - 2-yl) -ethyl] -benzenesulfonyl} - nitrile; (E) {4 -[1 -Methyl (5 -methyl -benzoxazol yl) -ethyl] - benzenesulfonyl} -acrylonitrile; (E) {4 -[1 -Methyl (5 l -oxazol yl) -ethyl] - benzenesulfonyl} -acrylonitrile; Cyclohexanecarboxylic acid N' -{2 -[4 -((E) cyano -ethenesulfonyl) -phen yl] hyl - propionyl} -hydrazide; (E) {4 -[1 -(5 hexyl -[1,3,4]oxadiazol yl) methyl ] -benzenesulfonyl} - acrylonitrile; or a pharmaceutically acceptable salt form thereof.
43. A pharmaceutical composition comprising a compound of any one of cla ims 40, 41, or 42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
44. The use of a compound of any one of claims 40, 41, or 42, or a pharmaceutically acceptable salt thereof, or the use of the compositi on of claim 43, for the manufacture of a medicament for treating or reducing the risk of peritoneal carcinomatosis in a patient that has had an intra -abdominal cancer removed.
45. The use according to claim 44, wherein the intra -abdominal cancer is located at or near the colon, at or near the ovary, at or near the , at or near the stomach, or at or near the pancreas of the patient.
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