`
`oz~«zwe»
`
`/(/f/M/I/’
`
`PROVISIONAL APPLICATION COVER SHEET
`
`PTO/SB/16 (6-95)
`
`This is a request for filing a PROVISIONAL APPLICATION under 37 CFR 1.53(c)
`
`Docket Number
`LA50(PSP)
`
`LAST NAME
`
`Type a plus sign(+) inside this box —->
`
`INVENTOR(S)/APPLICANT(S)
`
`MIDDLE
`INITIAL
`
`RESIDENCE
`
`(CITY & STATE OR
`FOREIGN COUNTRY)
`
`
`
`
`
`
`
`
`Robl
`
`Jeffrey
`
`A.
`
`Newtown, PA, USA
`
`
`
`00/01/soIllillllllllllllllllllllllllllmllll
`
`
`
`
`
`
`TITLE OF THE INVENTION (280 CHARACTERS MAX)
`
`
` CYCLOPROPYL-FUSED PYRROLIDINE—~BASED INHIBITORS OF DIPEPTIDYL PEPTIDASE IV
`AND METHOD
`
`CORRESPONDENCE ADDRESS
`
` BURTON RODNEY
`PATENT DEPARTMENT
`
`BRISTOL—MYERS SQUIBB COMPANY
`PO BOX 4000
`
`PRINCETON, NJ 08543-4000
`
`
`
`
`
`
`
`
`
`A
`
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`
`
`59 Number ofPages
`
`E] Drawing(s)
`
`El Number ofSheets
`
`E Othcflspccify)
`
`EXPRESS MAIL NO. EM069782125US
`
`
`
`METHOD OF PAYMENT
`The Commissioner is hereby authorized to charge filing fees and credit Deposit Account Number 19-
`3880. The Provisional Filing Fee Amount is ($)150.00. The Commissioner is hereby authorized to charge
`any additional fees which may be required except the Issue Fee, or credit any overpayment to Deposit
`, Account 19~3880.
`
`
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1027, p. 1 of 62
`
`0001
`0001
`
`EXHIBIT
`
`Ex. 1027
`
`Ex. 1027
`
`
`
`Docket No.2 LA50(PSP)
`
`-2-
`
`The invention was made by an agency of the United States Government or under a contract with an agency of
`the United States Government.
`
`No.
`
`El
`
`Yes, the name of the U.S. Government agency and the Government contract number are:
`
`Respectfully submitted,
`
`SIGNATUREéafi flz flaw DATE474% /0 zaao
`
`TYPED OR PRINTED NAME
`
`John M. Kilcoyne
`
`hereto.
`
`REGISTRATION No. 33,100
`
`TELEPHONE NO. (609) 252-5909
`
`El Additional inventors are being named on separately numbered sheets attached
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-IPRZO16-01104- Ex. 1027, p. 2 of 62
`
`0002
`0002
`
`
`
`LASO (PSP)
`
`EXPRESS MAIL NO:
`
`EM069782l25US
`
`CYCLOPROPYL-FUSED PYRROLIDINE-BASED INHIBITORS OF
`
`DIPEPTIDYL PEPTIDASE IV AND METHOD
`
`Field of the Invention
`
`The present invention relates to cyclopropyl—fused
`
`pyrrolidine—based inhibitors of dipeptidyl peptidase IV
`
`(DP—4), and to a method for treating diabetes, especially
`
`Type II diabetes, as well as hyperglycemia, Syndrome X,
`
`diabetic complications, hyperinsulinemia, obesity,
`
`10
`
`atherosclerosis and related diseases, as well as various
`
`immunomodulatory diseases and chronic inflammatory bowel
`
`disease, employing such cyclopropyl—fused pyrrolidines
`
`alone or in combination with another type antidiabetic
`
`agent.
`
`15
`
`20
`
`Background of the Invention
`
`Depeptidyl peptidase IV (DP—4)
`
`is a membrane bound
`
`non—clasical serine aminodipeptidase which is located in
`
`a variety of tissues (intestine,
`
`liver,
`
`lung, kidney) as
`
`well as on circulating T—lymphocytes
`
`(where the enzyme is
`
`known as CD—26).
`
`It is responsible for the metabolic
`
`cleavage of certain endogenous peptides (GLP—l(7—36),
`
`glucagon)
`
`in Vivo and has demonstrated proteolytic
`
`activity against a variety of other peptides (GHRH, NPY,
`
`25
`
`GLP—2, VIP)
`
`in vitro.
`
`GLP—l(7—36)
`
`is a 29 amino—acid peptide derived by
`
`post—translational processing of proglucagon in the small
`
`intestine.
`
`GLP—l(7—36) has multiple actions in Vivo
`
`including the stimulation of insulin secretion,
`
`inhibition of glucagon secretion,
`
`the promotion of
`
`satiety, and the slowing of gastric emptying. Based on
`
`its physiological profile,
`
`the actions of GLP—l(7—36) are
`
`expected to be beneficial in the prevention and treatment
`
`of type II diabetes and potentially obesity.
`
`To support
`
`this claim, exogenous administration of GLP—l(7—36)
`
`(continous infusion)
`
`in diabetic patients has
`
`demonstrated efficacy in this patient population.
`
`30
`
`35
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1027, p. 3 of 62
`
`0003
`0003
`
`
`
`LA50
`
`(PSP)
`
`Unfortunately GLP—1(7—36)
`
`is degraded rapidly in vivo and
`
`has been shown to have a short half—life in vivo
`
`(t1/2~1.5 min).
`
`Based on a study of genetically bred DP-
`
`4 KO mice and on in vivo/in vitro studies with selective
`
`DP—4 inhibitors, DP—4 has been shown to be the primary
`
`degrading enzyme of GLP—1(7—36)
`
`in vivo.
`
`GLP—1(7—36)
`
`is
`
`degraded by DP—4 efficiently to GLP—1(9—36), which has
`
`been speculated to act as a physiological antagonist to
`
`GLP-1(7—36) .
`
`Thus,
`
`inhibition of DP—4 in vivo should
`
`potentiate endogenous levels of GLP—1(7—36) and attenuate
`
`formation of its antagonist GLP-1(9—36) and thus serve to
`
`ameliorate the diabetic condition.
`
`
`Description of the Invention
`
`In accordance with the present invention,
`
`cyclopropyl—fused pyrrolidine—based compounds are
`
`provided which inhibit DP—4 and have the structure
`I
`
`10
`
`15
`
`20
`
`wherein x is O or 1 and y is O or 1
`
`(provided that
`
`R4
`
`o
`
`x
`
`X = 1 when y = 0 and
`
`x = 0 when y = 1);
`
`n is O or 1;
`
`X is H or CN (that is cyano);
`
`25
`
`R1, R2, R3 and R3 are the same or different and are
`
`independently selected from H, alkyl, alkenyl, alkynyl,
`
`cycloalkyl, cycloalkylalkyl, bicycloalkyl,
`
`bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl,
`
`cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
`
`30
`
`cycloheteroalkyl and cycloheteroalkylalkyl, all
`
`optionally substituted through available carbon atoms
`
`with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo,
`
`alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy,
`
`alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,
`
`-2-
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1027, p. 4 of 62
`
`0004
`0004
`
`
`
`LASO (PSP)
`
`cycloalkylalkyl, polycycloalkyl, heteroarylamino,
`
`arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,
`
`hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted
`
`amino, alkylamino, dialkylamino,
`
`thiol, alkylthio,
`
`alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,
`
`alkynylaminocarbonyl, alkylaminocarbonyl,
`
`alkenylaminocarbonyl, alkylcarbonyloxy,
`
`alkyloarbonylamino, arylcarbonylamino,
`
`alkylsulfonylamino, alkylaminocarbonylamino,
`
`10
`
`alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl,
`
`alkylsulfinyl, sulfonamido or sulfonyl;
`
`and R1 and R9 may optionally be taken together to
`form —(CR%f)m— where m is 2 to 6, and R5 and R6 are the
`
`same or different and are independently selected from
`
`15
`
`hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl,
`
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,
`arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`
`cycloheteroalkylalkyl, alkylcarbonylamino,
`
`arylcarbonylamino, alkoxycarbonylamino,
`
`20
`
`aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or
`alkylaminocarbonylamino, or R1 and R4 may optionally be
`taken together to form —(CRH§)p— where p is 3 to 6, and
`
`R7 and R8 are the same or different and are independently
`
`selected from hydroxy, alkoxy, cyano, H, alkyl, alkenyl,
`
`25
`
`alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,
`
`arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`
`cyoloheteroalkylalkyl, alkylcarbonylamino,
`
`arylcarbonylamino, alkoxycarbonylamino,
`
`aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or
`alkylaminooarbonylamino, or optionally R? and R3 together
`
`30
`
`I-I“"N
`
`(
`
`1%)
`
`W
`
`with
`
`form a 5 to 7 membered ring containing a
`
`total of 2 to 4 heteroatoms selected from N, O, S, S0, or
`
`302;
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1027, p. 5 of 62
`
`0005
`0005
`
`
`
`LA50
`
`(PSP)
`
`or optionally R1 and R3 together with
`
`R4
`
`form a 4 to 8 membered cycloheteroalkyl ring wherein the
`
`cycloheteroalkyl ring has an optional aryl ring fused
`
`thereto or an optional 3
`
`to 7 membered cycloalkyl ring
`
`fused thereto;
`
`and including pharmaceutically acceptable salts
`
`thereof, and prodrug esters thereof, and all
`
`stereoisomers thereof.
`
`Thus,
`
`the compounds of formula I of the invention
`
`10
`
`include the following structures
`
`IA
`
`IB
`
`R3
`
`R2 R1
`
`/,N
`
`H
`
`11
`
`R4
`
`N
`
`o
`
`x
`
`_
`
`15
`
`In addition,
`
`in accordance with the present
`
`invention, a method is provided for treating diabetes,
`
`especially Type II diabetes, and related diseases such as
`insulin resistance, hyperglycemia, hyperinsulinemia,
`
`20
`
`Syndrome X, diabetic conplications, elevated blood levels
`of fatty acids or glycerol, obesity, hypertriglyceridemia
`
`and atherosclerosis, and immunomodulatory diseases
`
`including AIDS, host—versus—graft rejection, and
`
`arthritis, and chronic inflammatory bowel disease (such
`
`25
`
`as Crohn's disease and ulcerative colitis), wherein a
`
`therapeutically effective amount of a compound of
`
`structure I
`
`(which inhibits DP 4)
`
`is administered to a
`
`human patient in need of treatment.
`
`The conditions, diseases, and maladies collectively
`
`30
`
`referenced to as “Syndrome X” or Metabolic Syndrome are
`
`-4-
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1027, p. 6 of 62
`
`0006
`0006
`
`
`
`LA50
`
`(PSP)
`
`detailed in Johannsson J. Clin. Endocrinol. Metab., gg,
`
`727-734 (l997).
`
`In addition,
`
`in accordance with the present
`
`invention, a method is provided for treating diabetes and
`
`U1
`
`related diseases as defined above and hereinafter,
`
`wherein a therapeutically effective amount of a
`
`combination of a compound of structure I and one,
`
`two,
`
`three or more of other types of antidiabetic agent(s)
`
`and/or one,
`
`two or three or more other types of
`
`10
`
`therapeutic agent(s)
`in need of treatment.
`
`is administered to a human patient
`
`The conditions, diseases and maladies collectively
`
`referred to as “diabetic complications” include
`
`15
`
`20
`
`retinopathy, neuropathy and nephropathy, and other known
`
`complications of diabetes.
`The term “other type(s) of therapeutic agents” as
`
`employed herein refers to one or more antidiabetic agents
`
`(other than DP4 inhibitors of formula I), one or more
`
`anti—obesity agents, and/or one or more lipid—lowering
`
`agents (including anti—atherosclerosis agents).
`In the above method of the invention,
`the compound
`
`of structure I will be employed in a weight ratio to the
`
`antidiabetic agent or other type therapeutic agent
`
`(depending upon its mode of operation) within the range
`from about 0.01:1 to about 500:1, preferably from about
`
`25
`
`0.1:1 to about 100:1, more preferably from about 0.2:1 to
`
`about 10:1.
`
`Preferred are compounds of formula I wherein R3 is
`
`H or alkyl, R1 is H or alkyl, R2 is H or alkyl, n is 0, X
`
`is CN, X is 0 or 1 and y is 0 or 1.
`
`Most preferred are preferred compounds of formula I
`I
`as described above where X is C“ °r “CN ;
`
`and/or wherein the fused cyclopropyl group is
`
`identified as
`
`V .
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-IPRZO16-O1104- Ex. 1027, p. 7 of 62
`
`0007
`0007
`
`
`
`LA50 (PSP)
`
`Thus, preferred compounds of formula I of the
`
`invention will include the moiety
`
` 5
`
`10
`
`wherein R1 is alkyl, cycloalkyl or bicycloalkyl;
`
`[lS,2(2S),3S,5S]
`
`15
`
`(B)
`
`[1R,2S,3 (2S) ,5S]
`
`wherein R1 is alkyl, cycloalkyl or bicycloalkyl-
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-IPRZO16-01104- Ex. 1027, p. 8 of 62
`
`0008
`0008
`
`
`
`LASO (PSP)
`
`Detailed Description of the Invention
`
`Compounds of the structure I may be generated by
`
`the methods as shown in the following reaction schemes
`
`and the description thereof.
`
`Referring to Reaction Scheme 1, compound 1, where
`
`PG1 is a common amine protecting group such as Boc, Cbz,
`
`or FMOC and X1 is H or Cofif as set out below, may be
`
`generated by methods as described herein or in the
`
`literature (for example see Sagnard et al, Tet—Lett.,
`
`1995, 36, pp. 3148-3152, Tverezovsky et al, Tetrahedron,
`
`1997, 53, pp. 14773-14792, Hanessian et al, Bioorg. Med.
`
`Chem. Lett., 1998, 8, p. 2123-2128). Removal of the PG1
`
`group by conventional methods
`
`(e.g.
`
`(1) TFA or HC1 when
`
`PG1 is Boc, or
`
`(2) H2/Pd/C, TMSI when PG; is Cbz, or
`
`(3)
`
`Et2NH when PG1 is (FMOC) affords the free amine 2. Amine
`
`2 may be coupled to various protected amino acids such as
`
`3
`
`(where PG2 can be any of the PG1 protecting groups)
`
`using standard peptide coupling conditions (e.g.
`
`EDAC/HOAT,
`
`i—BuCOCOC1/TEA, PyBop/NMM)
`
`to afford the
`
`corresponding dipeptide 4. Removal of the amine
`
`protecting group PG; provides compound Ia of the
`invention where X=H.
`
`In the case where X1=COfi?
`
`(where R? is alkyl or
`
`aralkyl groups such as methyl, ethyl,
`
`t—butyl, or
`
`benzyl),
`
`the ester may be hydrolyzed under a variety of
`
`conditions,
`
`for example with aqueous NaOH in a suitable
`
`solvent such as methanol, THF, or dioxane,
`
`to provide the
`
`acid 5. Conversion of the acid group to the primary
`
`carboxamide, affording 6, may be effected by activation
`
`of the acid group (e.g. employing i—BuOCOC1/TEA or EDAC)
`
`followed by treatment with NH3 or an ammonia equivalent
`
`in a solvent such as dioxane, ether, or methanol.
`
`The
`
`amide functionality may be converted to the nitrile group
`
`by a variety of standard conditions (e.g.
`
`POCl3/pyridine/imidazole or cyanuric chloride/DMF)
`
`to
`
`give 7. Finally,
`
`removal of the PG2 protecting group
`
`similar to above provides compound of the invention Ib.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:28)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1027, p. 9 of 62
`
`0009
`0009
`
`
`
`LA5o
`
`(PSP)
`
`In a different sequence (Scheme 2), compound 1
`
`where X1 is con? may be saponified to the acid and
`
`subsequently amidated as described above to give amide 8.
`Removal of the PG; group followed by peptide coupling to
`
`3 affords compound 6, an intermediate in the synthesis of
`Ib.
`
`Alternately,
`
`the carboxamide group in 8 may be
`
`converted to the nitrile as described above to give
`
`compound 9. Deprotection of PG1 affords 10 which may be
`subject to standard peptide coupling conditions to afford
`7, an intermediate in the synthesis of Ib.
`Compound 10
`may also be generated by oxidation of the amine 2
`(e.g.
`NCS)
`followed by hydrolysis and subsequent cyanide
`treatment.
`Compound 10 may be obtained as a mixture of
`stereoisomers or a single isomer/diastereomer which may
`
`10
`
`15
`
`be epimerized (employing conventional procedures)
`
`to
`
`afford a mixture of stereoisomers.
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:19)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 10 of 62
`
`0010
`0010
`
`
`
`LASO (PSP)
`
`Scheme 1
`
`Hx
`'1' My
`PG1/ Y
`1
`X1
`
`x‘ =H,CO2R9
`
`2
`
`( )/<‘
`Ix
`
`3 R1 R
`
`'
`PG; O
`
`X1
`
`4
`
`R
`
`)y
`
`saponify
`x‘ = co,R
`
`
`deprotect
`
`2
`
`OH
`
`3R1 RR\
`(N W‘
`, H
`P62 0
`3
`
`HNY V
`Peptide coupling
`2
`X1
`conditions
`
`deprotect
`
`1
`=
`
`X
`
`H
`
`R3 R1
`\N
`H
`
`R2
`
`%
`
`)y
`
`(
`
`)x
`,1,
`\/
`
`(
`
`‘a
`
`O
`
`R2
`
`R3 R1
`‘N
`,
`PG2 0
`
`( )/<‘
`X
`:1:
`(
`
`)y
`
`CO2”
`
`5
`
`R2
`
`1
`.
`3 R
`amldate
`———> R \N
`I
`PG2 o
`
`( )x/<1
`,
`(
`N
`Y
`CONH2
`
`)
`
`v
`
`6
`
`nitrile formation
`(e.g POCI3, imidazole, pyridine
`O!‘
`
`cyanuric chloride, DMF
`
`\
`(l)’‘
`R1R2
`R3\“>ST"Y( ”
`
`'
`PG; 0
`7
`
`ON
`
`deprotect
`’
`
`\
`(|)x
`3R1 R2
`R‘“>.\W"Y( ”
`
`H
`
`CN
`
`°
`lb
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 11 of 62
`
`0011
`001 1
`
`
`
`LASO (PSP)
`
`Scheme 2
`
`lb
`
`1.deprotect
`2.
`1 R2
`R1F§>i\H,oH
`a 0 3
`pepfideccupfing
`conditions
`
`I m
`
`——————————>— 6———>»
`
`() ———————>»
`
`I
`
`(RX
`y
`PG1’N\r
`1
`002R”
`
`1-saponify
`2. amidate
`
`I
`
`()x/<1
`PG1/Nxl/( )3’
`8
`CONH2
`
`?itri|e
`onnaflon
`
`R‘ R2
`
`d
`
`t
`
`R3\wlflfilrol-!
`t
`/<1
`3
`( )/<l
`epro ec
`( )x
`PG2 O
`X
`|
`/N ()y ———>H|1l H ————————>7—-—>lb
`\T’
`\T/
`pepfidecoupfing
`V
`condmons
`
`PG1
`
`
`
`([>21
`
`HN\/( )y
`
`2
`
`5
`
`In a like manner, B—amino acids such as
`
`N
`
`PG2/
`
`CH
`
`W 0
`
`10
`
`15
`
`the free amine of 8, or 10 to give
`may be coupled with 2,
`the corresponding amides which may be converted to
`compound Ia or Ib following the same chemistry.
`Unless otherwise indicated,
`the term "lower
`
`alkyl", "alkyl" or "alk" as employed herein alone or as
`part of another group includes both straight and branched
`chain hydrocarbons, containing 1 to 20 carbons,
`preferably 1 to 10 carbons, more preferably 1 to 8
`carbons,
`in the normal chain, such as methyl, ethyl,
`propyl,
`isopropyl, butyl,
`t—butyl,
`isobutyl, pentyl,
`hexyl,
`isohexyl, heptyl, 4,4—dimethylpentyl, octyl,
`2,2,4—trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl,
`
`-10..
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1027, p. 12 of 62
`
`0012
`0012
`
`
`
`LA50
`
`(PSP)
`
`the various branched chain isomers thereof, and the like
`
`as well as such groups including 1 to 4 substituents such
`
`as halo, for example F, Br, C1 or I or CF3, alkyl,
`
`alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,
`arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,
`cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl,
`
`heteroaryl, heteroaryloxy, heteroarylalkyl,
`
`heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,
`
`aryloxyaryl, alkylamido, alkanoylamino,
`arylcarbonylamino, nitro, cyano,
`thiol, haloalkyl,
`
`10
`
`trihaloalkyl and/or alkylthio.
`
`Unless otherwise indicated,
`
`the term "cycloalkyl"
`
`as employed herein alone or as part of another group
`includes saturated or partially unsaturated (containing 1
`
`15
`
`or 2 double bonds) cyclic hydrocarbon groups containing 1
`
`including monocyclic alkyl, bicyclic alkyl
`to 3 rings,
`(or bicycloalkyl) and tricyclic alkyl, containing a total
`of 3
`to 20 carbons forming the ring, preferably 3 to 10
`
`carbons,
`
`forming the ring and which may be fused to 1 or
`
`20
`
`2 aromatic rings as described for aryl, which includes
`cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl,
`
`25
`
`30
`
`CO A,
`Q
`(D (5, @,
`
`any of which groups may be optionally substituted with 1
`to 4 substituents such as halogen, alkyl, alkoxy,
`hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl,
`alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino,
`amino, nitro, cyano,
`thiol and/or alkylthio and/or any of
`
`the substituents for alkyl.
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 13 of 62
`
`0013
`0013
`
`
`
`LA50
`
`(PSP)
`
`The term “cycloalkenyl” as employed herein alone
`
`or as part of another group refers to cyclic hydrocarbons
`
`containing 3 to 12 carbons, preferably 5 to 10 carbons
`
`and 1 or 2 double bonds. Exemplary cycloalkenyl groups
`
`include cyclopentenyl, cyclohexenyl, cycloheptenyl,
`
`cyclooctenyl, cyclohexadienyl, and cycloheptadienyl,
`
`which may be optionally substituted as defined for
`
`cycloalkyl.
`
`The term “cycloalkylene” as employed herein refers
`
`10
`
`to a “cycloalkyl” group which includes free bonds and
`
`thus is a linking group such as
`
`and the like, and may Optionally be
`
`substituted as defined above for “cycloalkyl”.
`
`The term "alkanoyl" as used herein alone or as
`
`15
`
`part of another group refers to alkyl linked to a
`
`carbonyl group.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkenyl" or “alkenyl" as used herein by itself or as part
`of another group refers to straight or branched chain
`radicals of 2 to 20 carbons, preferably 2 to 12 carbons,
`
`20
`
`25
`
`30
`
`and more preferably 1 to 8 carbons in the normal chain,
`which include one to six double bonds in the normal
`
`chain, such as vinyl, 2—propenyl, 3—butenyl, 2—butenyl,
`4—pentenyl, 3—pentenyl, 2-hexenyl, 3—hexenyl, 2—heptenyl,
`3—heptenyl, 4—heptenyl, 3—octenyl, 3—nonenyl, 4—decenyl,
`3—undecenyl, 4—dodecenyl, 4,8,l2—tetradecatrienyl, and
`the like, and which may be optionally substituted with l
`to 4 substituents, namely, halogen, haloalkyl, alkyl,
`alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
`amino, hydroxy, heteroaryl, cycloheteroalkyl,
`alkanoylamino, alkylamido, arylcarbonyl—amino, nitro,
`cyano,
`thiol, alkylthio and/or any of the alkyl
`substituents set out herein.
`
`Unless otherwise indicated,
`
`the term "lower
`
`35
`
`alkynyl" or "alkynyl" as used herein by itself or as part
`of another group refers to straight or branched chain
`
`-12-
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 14 of 62
`
`0014
`0014
`
`
`
`LASO (PSP)
`
`radicals of 2 to 20 carbons, preferably 2 to 12 carbons
`
`and more preferably 2 to 8 carbons in the normal chain,
`
`which include one triple bond in the normal chain, such
`
`as 2—propynyl, 3—butynyl, 2—butynyl, 4—pentynyl, 3-
`
`pentynyl, 2—hexynyl, 3—hexynyl, 2—heptynyl, 3—heptynyl,
`
`4—heptynyl, 3—octynyl, 3—nonynyl, 4—decynyl,3—undecynyl,
`
`4—dodecynyl and the like, and which may be optionally
`
`substituted with l to 4 substituents, namely, halogen,
`
`haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,
`
`10
`
`arylalkyl, cycloalkyl, amino, heteroaryl,
`cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,
`arylcarbonylamino, nitro, cyano,
`thiol, and/or alkylthio,
`and/or any of the alkyl substituents set out herein.
`The terms "arylalkenyl" and ”arylalkynyl" as used
`
`15
`
`alone or as part of another group refer to alkenyl and
`
`alkynyl groups as described above having an aryl
`substituent.
`
`Where alkyl groups as defined above have single
`
`20
`
`bonds for attachment to other groups at two different
`
`carbon atoms,
`
`they are termed "alkylene" groups and may
`
`optionally be substituted as defined above for "alkyl".
`Where alkenyl groups as defined above and alkynyl
`
`groups as defined above, respectively, have single bonds
`for attachment at two different carbon atoms,
`they are
`
`25
`
`termed "alkenylene groups“ and "alkynylene groups",
`
`respectively, and may optionally be substituted as
`
`defined above for "alkenyl" and "alkynyl".
`
`The term "halogen" or "halo" as used herein alone
`
`30
`
`or as part of another group refers to chlorine, bromine,
`fluorine, and iodine as well as CF3, with chlorine or
`
`fluorine being preferred.
`
`The term "metal
`ion" refers to alkali metal
`ions
`such as sodium, potassium or lithium and alkaline earth
`metal ions such as magnesium and calcium, as well as zinc
`
`35
`
`and aluminum.
`
`
`
`
`$31
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 15 of 62
`
`0015
`0015
`
`
`
`LA5o (PSP)
`
`Unless otherwise indicated,
`
`the term "aryl" as
`
`employed herein alone or as part of another group refers
`
`to monocyclic and bicyclic aromatic groups containing 6
`
`to 10 carbons in the ring portion (such as phenyl or
`
`naphthyl including l—naphthyl and 2—naphthyl) and may
`
`optionally include one to three additional rings fused to
`
`a carbocyclic ring or a heterocyclic ring (such as aryl,
`
`cycloalkyl, heteroaryl or cycloheteroalkyl rings
`
`for example
`
`10
`
`%. .%_
`
`.®— , wa
`
`<:b— ,
`
`<21}. w ,
`
`<Z3©-. <13‘ , QC“
`
`15
`
`20
`
`25
`
`and may be optionally substituted through available
`
`carbon atoms with 1, 2, or 3 groups selected from
`
`hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy,
`
`haloalkoxy, alkenyl,
`
`trifluoromethyl,
`
`trifluoromethoxy,
`
`alkynyl, cycloalkyl—alkyl, cycloheteroalkyl,
`
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`
`aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo,
`
`heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl,
`
`heteroaryloxy, hydroxy, nitro, cyano, amino, substituted
`
`amino wherein the amino includes 1 or 2 substituents
`
`(which are alkyl, aryl or any of the other aryl compounds
`
`mentioned in the definitions),
`
`thiol, alkylthio,
`
`arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio,
`
`alkylcarbonyl, arylcarbonyl, alkyl—aminocarbonyl,
`
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`
`alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,
`
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,
`
`
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 16 of 62
`
`0016
`0016
`
`
`
`LA50
`
`(PSP)
`
`arylsulfonylamino or arylsulfon—aminocarbonyl and/or any
`
`of the alkyl substituents set out herein.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkoxy", "alkoxy", ”aryloxy" or "aralkoxy" as employed
`
`herein alone or as part of another group includes any of
`
`the above alkyl, aralkyl or aryl groups linked to an
`
`oxygen atom.
`
`Unless otherwise indicated,
`
`the term "substituted
`
`amino" as employed herein alone or as part of another
`
`group refers to amino substituted with one or two
`substituents, which may be the same or different, such as
`
`alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl,
`cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or
`thioalkyl.
`These substituents may be further substituted
`with a carboxylic acid and/or any of the R1 groups or
`substituents for R1 as set out above.
`In addition,
`the
`
`amino substituents may be taken together with the
`
`nitrogen atom to which they are attached to form
`1—pyrrolidinyl, 1—piperidinyl, 1—azepinyl, 4—morpholinyl,
`4—thiamorpholinyl,
`l~piperazinyl, 4—alkyl—l—piperazinyl,
`4—arylalkyl—l—piperazinyl, 4—diarylalkyl~1—piperazinyl,
`1—pyrrolidinyl,
`l—piperidinyl, or l—azepinyl, optionally
`substituted with alkyl, alkoxy, alkylthio, halo,
`
`10
`
`15
`
`20
`
`
`
`25
`
`trifluoromethyl or hydroxy.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkylthio", alkylthio",
`
`"arylthio" or ”aralkylthio" as
`
`employed herein alone or as part of another group
`includes any of the above alkyl, aralkyl or aryl groups
`linked to a sulfur atom.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkylamino", "alkylamino", "arylamino", or
`"arylalkylamino" as employed herein alone or as part of
`another group includes any of the above alkyl, aryl or
`
`arylalkyl groups linked to a nitrogen atom.
`Unless otherwise indicated,
`the term "acyl" as
`
`employed herein by itself or part of another group, as
`
`30
`
`35
`
`-15-
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 17 of 62
`
`0017
`0017
`
`
`
`LASO (PSP)
`
`defined herein, refers to an organic radical linked to a
`9
`( E )
`carbonyl
`any of the R1 groups attached to a carbonyl, such as
`
`group; examples of acyl groups include
`
`alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,
`
`cycloalkanoyl, cycloheteroalkanoyl and the like.
`
`Unless otherwise indicated,
`
`the term
`
`“cycloheteroalkyl” as used herein alone or as part of
`
`another group refers to a 5-, 6- or 7—membered saturated
`
`or partially unsaturated ring which includes 1 to 2
`
`hetero atoms such as nitrogen, oxygen and/or sulfur,
`
`linked through a carbon atom or a heteroatom, where
`
`possible, optionally via the linker (CHflr
`
`(where r is 1,
`
`2 or 3), such as
`
`N
`
`.|—[ Q O\_'_/
`
`/N , <I°:<E'j1~,EZ1=
`
`°‘W
`N
`«a/CDIN},
`
`/N
`
`°,
`
`(L/l
`
`and the like.
`
`The above groups may include l to 4
`
`substituents such as alkyl, halo, oxo and/or any of of
`
`the alkyl substituents set out herein.
`
`In addition, any
`
`of the cycloheteroalkyl rings can be fused to a
`
`cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
`
`Unless otherwise indicated,
`
`the term "heteroaryl"
`
`as used herein alone or as part of another group refers
`
`to a 5- or 6— membered aromatic ring which includes 1, 2,
`
`
`
`10
`
`15
`
`20
`
`25
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)(cid:21)
`Sun-Amneal-|PR2016-O1104- Ex. 1027, p. 18 of 62
`
`0018
`0018
`
`
`
`LA5O (PSP)
`
`3 or 4 hetero atoms such as nitrogen, oxygen or
`
`sulfur,and such rings fused to an aryl, cycloalkyl,
`
`heteroaryl or cycloheteroalkyl ring (e.g.
`
`benzothiophenyl,
`
`indolyl), and includes possible N-
`
`oxides.
`
`The heteroaryl group may optionally include 1 to
`
`4 substituents such as any of the substituents set out
`
`above for alkyl.
`
`Examples of heteroaryl groups include
`
`the following:
`
`O
`
`<:
`\
`
`\7
`I’
`
`9
`
`0
`
`’/ l__
`9 $ I
`
`’
`
`<92» »</02> »<//7.;> Q
`
`and the like.
`
`10
`
`15
`
`
`
`The term "cycloheteroalkylalkyl" as used