HETEROCYCLIC INHIBITORS OF ATR KINASE
20200102296 ยท 2020-04-02
Inventors
- Maria Emilia Di Francesco (Houston, TX)
- Philip Jones (Houston, TX)
- Christopher Lawrence Carroll (Houston, TX)
- Jason Bryant Cross (Pearland, TX)
- Suyambu Kesava Vijayan Ramaswamy (Houston, TX)
- Michael Garrett Johnson (San Francisco, CA)
- Sarah Lively (San Carlos, CA)
- David Lapointe (Oakland, CA)
Cpc classification
A61K45/06
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
C07D413/04
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D413/04
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
Abstract
The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of ATR kinase for the treatment or prevention of cancer.
Claims
1.-101. (canceled)
102. A compound having formula: ##STR00349## or a salt thereof.
103. The compound as recited in claim 102, having formula: ##STR00350## or a salt thereof.
104. A pharmaceutical composition comprising a compound as recited in claim 103, or a salt thereof, together with a pharmaceutically acceptable carrier.
105. A method of sensitizing cells to DNA-damaging agents comprising administering to a patient in need thereof, an effective amount of compound as recited in claim 103, or a salt thereof.
106. A method of preventing cell repair from DNA damage comprising administering to a patient a compound as recited in claim 103, or a salt thereof.
107. A method of inhibition of ATR kinase comprising contacting ATR kinase with a compound as recited in claim 103, or a salt thereof.
108. A method of treatment of an ATR kinase-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in claim 103, or a salt thereof, to a patient in need thereof.
109. The method as recited in claim 108, wherein the disease is cancer.
110. The method as recited in claim 109, wherein the cancer is a chemotherapy-resistant cancer.
111. The method as recited in claim 109, wherein the cancer is a radiotherapy-resistant cancer.
112. The method as recited in claim 109, wherein the cancer is an ALT-positive cancer.
113. The method as recited in claim 109, wherein the cancer is a sarcoma.
114. The method as recited in claim 109, wherein the cancer is chosen from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.
115. The method as recited in claim 109, wherein the cancer is chosen from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.
116. The method as recited in claim 109, further comprising administering to the patient another therapeutic agent, wherein the other therapeutic agent inhibits or modulates a base excision repair protein.
117. The method of claim 109, wherein the method further comprises administering non-chemical methods of cancer treatment.
Description
EMBODIMENT I-1
[0552] A compound of structural Formula (I):
##STR00064##
[0553] or a salt thereof, wherein: [0554] R.sup.1 and R.sup.2 are independently selected from C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl, C.sub.3-6 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with one or more R.sup.5 groups, or R.sup.1 and R.sup.2, together with the sulfur to which they are both attached, form a heterocycloalkyl ring which is optionally substituted with one or more R.sup.5 groups; [0555] R.sup.3 is selected from hydrogen, C.sub.1-6alkyl, and C.sub.1-6haloalkyl; R.sup.4 is selected from C.sub.5-10aryl and C.sub.5-10heteroaryl, each of which is optionally substituted with one or more R.sup.6 groups; [0556] each R.sup.5 is independently selected from NR.sup.8R.sup.9, halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyalkyl, OR.sup.8, NR.sup.7C(O)R.sup.8, NR.sup.7C(O)OR.sup.8, NR.sup.7C(O)NR.sup.8R.sup.9, C(O)R.sup.8, C(O)OR.sup.8, and C(O)NR.sup.8R.sup.9; [0557] each R.sup.6 is independently selected from NR.sup.11R.sup.12, halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyalkyl, OR.sup.11, NR.sup.10C(O)R.sup.11, NR.sup.10C(O)OR.sup.11, NR.sup.10C(O)NR.sup.11R.sup.12, C(O)R.sup.11, C(O)OR.sup.11, and C(O)NR.sup.11R.sup.12; [0558] each R.sup.7, R.sup.8 and R.sup.9 is independently selected from hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, and heterocycloalkyl and is optionally substituted with halo, hydroxy, C.sub.1-3alkyl, C.sub.1-3 haloalkyl, and C.sub.1-3alkoxy; or any two of R.sup.7, R.sup.8 and R.sup.9, together with the atom to which they are both attached can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and [0559] each R.sup.10, R.sup.11 and R.sup.12 is independently selected from hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, and heterocycloalkyl and is optionally substituted with one or more groups selected from halo, hydroxy and alkoxy; or any two of R.sup.10, R.sup.11 and R.sup.12, together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring.
EMBODIMENT I-2
[0560] The compound as recited in Embodiment I-1, wherein R.sup.3 is C.sub.1-6alkyl.
EMBODIMENT I-3
[0561] The compound as recited in Embodiment I-2, wherein R.sup.3 is methyl.
EMBODIMENT II-4
[0562] A compound of structural Formula (II):
##STR00065##
[0563] or a salt thereof, wherein: [0564] R.sup.1 and R.sup.2 are independently selected from C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl, C.sub.3-6 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with one or more R.sup.5 groups, or R.sup.1 and R.sup.2, together with the sulfur to which they are both attached, form a heterocycloalkyl ring which is optionally substituted with one or more R.sup.5 groups;
[0565] R.sup.3 is selected from hydrogen, C.sub.1-6alkyl, and C.sub.1-6haloalkyl; R.sup.4 is selected from C.sub.5-10aryl or C.sub.5-10heteroaryl and is optionally substituted with one or more R.sup.6 groups; [0566] each R.sup.5 is independently selected from NR.sup.8R.sup.9, halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyalkyl, OR.sup.8, NR.sup.7C(O)R.sup.8, NR.sup.7C(O)OR.sup.8, NR.sup.7C(O)NR.sup.8R.sup.9, C(O)R.sup.8, C(O)OR.sup.8, and C(O)NR.sup.8R.sup.9; [0567] each R.sup.6 is independently selected from NR.sup.11R.sup.12, halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyalkyl, OR.sup.11, NR.sup.10C(O)R.sup.11, NR.sup.10C(O)OR.sup.11, NR.sup.10C(O)NR.sup.11R.sup.12, C(O)R.sup.11, C(O)OR.sup.11, and C(O)NR.sup.11R.sup.12; [0568] each R.sup.7, R.sup.8 and R.sup.9 is independently selected from hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl and heterocycloalkyl and is optionally substituted with halo, hydroxy, C.sub.1-3alkyl, C.sub.1-3 haloalkyl and C.sub.1-3alkoxy; or any two of R.sup.7, R.sup.8 and R.sup.9, together with the atom to which they are both attached can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and [0569] each R.sup.10, R.sup.11 and R.sup.12 is independently selected from hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl and heterocycloalkyl and is optionally substituted with one or more groups selected from halo, hydroxy and alkoxy; or any two of R.sup.10, R.sup.11 and R.sup.12, together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring.
EMBODIMENT II-5
[0570] The compound as recited in Embodiment II-4, wherein R.sup.3 is C.sub.1-6alkyl.
EMBODIMENT II-6
[0571] The compound as recited in Embodiment II-5, wherein R.sup.3 is methyl.
EMBODIMENT II-7
[0572] The compound as recited in Embodiment II-6, wherein R.sup.4 is C.sub.5-10heteroaryl and is optionally substituted with one or more R.sup.6 groups.
EMBODIMENT II-8
[0573] The compound as recited in Embodiment II-7, wherein R.sup.4 is selected from indole, pyrrolopyridine, pyrazolopyridine, imidazolopyridine, pyrrolopyrazine, pyrazolopyrazine, pyrrolopyrimidine, pyrazolopyrimidine, imidazolopyrimidine, pyrrolopyridazine, pyrazolopyridazine, and imidazolopyridazine, and is optionally substituted with one or more R.sup.6 groups.
EMBODIMENT II-9
[0574] The compound as recited in Embodiment II-8, wherein R.sup.4 is selected from 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-c]pyridazine, 7H-pyrrolo[2,3-d]pyrimidine, and 5H-pyrrolo[2,3-b]pyrazine and is optionally substituted with one, two, or three R.sup.6 groups.
EMBODIMENT II-10
[0575] The compound as recited in Embodiment II-9, wherein R.sup.4 is 1H-pyrrolo[2,3-b]pyridine and is optionally substituted with one or two R.sup.6 groups.
EMBODIMENT II-11
[0576] The compound as recited in Embodiment II-10, wherein each R.sup.6 is independently selected from NR.sup.11R.sup.12, halogen, cyano, hydroxy, oxo, OR.sup.11, NR.sup.10C(O)R.sup.11, NR.sup.10C(O)OR.sup.11, NR.sup.10C(O)NR.sup.11R.sup.12, C(O)R.sup.11, C(O)OR.sup.11, and C(O)NR.sup.11R.sup.12.
EMBODIMENT II-12
[0577] The compound as recited in Embodiment II-11, wherein each R.sup.6 is independently selected from NR.sup.11R.sup.12, halogen, cyano, hydroxy, and oxo.
EMBODIMENT II-13
[0578] The compound as recited in Embodiment II-12, wherein R.sup.4 is selected from
##STR00066##
EMBODIMENT II-14
[0579] The compound as recited in Embodiment II-13, wherein [0580] R.sup.1 and R.sup.2 are independently selected from C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl, C.sub.3-6 heterocycloalkyl, aryl, and heteroaryl and are optionally substituted with one or two R.sup.5 groups, or R.sup.1 and R.sup.2, together with the sulfur to which they are both attached, form a heterocycloalkyl ring which is optionally substituted with one or two R.sup.5 groups; [0581] each R.sup.5 is independently selected from NR.sup.8R.sup.9, halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyalkyl, OR.sup.8, NR.sup.7C(O)R.sup.8, NR.sup.7C(O)OR.sup.8, NR.sup.7C(O)NR.sup.8R.sup.9, C(O)R.sup.8, C(O)OR.sup.8, and C(O)NR.sup.8R.sup.9.
EMBODIMENT II-15
[0582] The compound as recited in Embodiment II-14, wherein each R.sup.5 is independently selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyalkyl, OR.sup.8, NR.sup.7C(O)R.sup.8, NR.sup.7C(O)OR.sup.8, NR.sup.7C(O)NR.sup.8R.sup.9, C(O)R.sup.8, C(O)OR.sup.8, and C(O)NR.sup.8R.sup.9.
EMBODIMENT II-16
[0583] The compound as recited in Embodiment II-15, wherein each R.sup.5 is independently selected from C(O)R.sup.8, C(O)OR.sup.8, and C(O)NR.sup.8R.sup.9.
EMBODIMENT II-17
[0584] The compound as recited in Embodiment II-16, wherein R.sup.1 and R.sup.2 are independently selected from C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl, C.sub.3-6heterocycloalkyl, aryl, and heteroaryl and are optionally substituted with one or two R.sup.5 groups.
EMBODIMENT II-18
[0585] The compound as recited in Embodiment II-17, wherein R.sup.1 and R.sup.2 are independently selected from C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl, and C.sub.3-6heterocycloalkyl and are optionally substituted with one or two R.sup.5 groups.
EMBODIMENT 11-19
[0586] The compound as recited in Embodiment II-17, wherein R.sup.1 and R.sup.2 are independently selected from C.sub.1-4alkyl and C.sub.3-6cycloalkyl.
EMBODIMENT II-20
[0587] The compound as recited in Embodiment II-17, wherein R.sup.1 and R.sup.2, together with the sulfur to which they are both attached, forms a heterocycloalkyl ring and is optionally substituted with one or two R.sup.5 groups.
EMBODIMENT C-21
[0588] The compound as recited in Embodiment I-1, wherein the structure is selected from
##STR00067## ##STR00068##
EMBODIMENT C-22
[0589] The compound as recited in Embodiment I-1 for use as a medicament.
EMBODIMENT C-23
[0590] The compound as recited in Embodiment I-1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of ATR kinase.
EMBODIMENT C-24
[0591] The compound as recited in Embodiment C-23, wherein the disease is cancer.
EMBODIMENT C-25
[0592] The compound as recited in Embodiment C-24, wherein the cancer is a chemotherapy-resistant cancer.
EMBODIMENT C-26
[0593] The compound as recited in Embodiment C-24, wherein the cancer is a radiotherapy-resistant cancer.
EMBODIMENT C-27
[0594] The compound as recited in Embodiment C-24, wherein the cancer is an ALT-positive cancer.
EMBODIMENT C-28
[0595] The compound as recited in Embodiment C-24, wherein the cancer is a sarcoma.
EMBODIMENT C-29
[0596] The compound as recited in Embodiment C-24, wherein the cancer is selected from osteosarcoma and glioblastoma.
EMBODIMENT C-30
[0597] The compound as recited in Embodiment C-24, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.
EMBODIMENT C-31
[0598] The compound as recited in Embodiment C-24, wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.
EMBODIMENT C-32
[0599] The compound as recited in Embodiment C-24, wherein the cancer has a defect in a base excision repair protein.
EMBODIMENT C-33
[0600] A pharmaceutical composition comprising a compound as recited in Embodiment I-1 together with a pharmaceutically acceptable carrier.
EMBODIMENT M-34
[0601] A method of sensitizing cells to DNA-damaging agents comprising administering to a patient a compound as recited in Embodiment I-1.
EMBODIMENT M-35
[0602] A method of preventing cell repair from DNA damage comprising administering to a patient a compound as recited in Embodiment I-1.
EMBODIMENT M-36
[0603] A method of inhibition of ATR kinase comprising contacting ATR kinase with a compound as recited in Embodiment I-1.
EMBODIMENT M-37
[0604] A method of treatment of an ATR kinase-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in Embodiment I-1 to a patient in need thereof.
EMBODIMENT M-38
[0605] The method as recited in Embodiment M-37, wherein the disease is cancer.
EMBODIMENT M-39
[0606] The method as recited in Embodiment M-38, wherein the cancer is a chemotherapy-resistant cancer.
EMBODIMENT M-40
[0607] The method as recited in Embodiment M-38, wherein the cancer is a radiotherapy-resistant cancer.
EMBODIMENT M-41
[0608] The method as recited in Embodiment M-38, wherein the cancer is an ALT-positive cancer.
EMBODIMENT M-42
[0609] The method as recited in Embodiment M-38, wherein the cancer is a sarcoma.
EMBODIMENT M-43
[0610] The method as recited in Embodiment M-38, wherein the cancer is selected from osteosarcoma and glioblastoma.
EMBODIMENT M-44
[0611] The method as recited in Embodiment M-38, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.
EMBODIMENT M-45
[0612] The method as recited in Embodiment M-38, wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.
EMBODIMENT M-46
[0613] The method as recited in Embodiment M-38, wherein the cancer has a defect in a base excision repair protein.
EMBODIMENT M-47
[0614] The method as recited in Embodiment M-38, wherein the cancer has defects in the ATM signaling cascade.
EMBODIMENT M-48
[0615] The method as recited in Embodiment M-47, wherein the defect is altered expression or activity of one or more of the following: TM, p53, CHK2, MRE11, RAD50, NBS 1, 53BP1, MDC1, H2AX, MCPH1/BRIT1, CTIP, or SMC1.
EMBODIMENT M-49
[0616] The method as recited in Embodiment M-38, further comprising administering to the patient another therapeutic agent, wherein the other therapeutic agent inhibits or modulates a base excision repair protein.
EMBODIMENT M-50
[0617] A method of treatment of an ATR kinase-mediated disease comprising the administration of:
[0618] a. a therapeutically effective amount of a compound as recited in Embodiment I-1; and
[0619] b. another therapeutic agent.
EMBODIMENT M-51
[0620] The method as recited in Embodiment M-50, wherein the other therapeutic agent is a CHK1 inhibitor.
EMBODIMENT M-52
[0621] The method as recited in Embodiment M-50, wherein the CHK1 inhibitor is selected from MK-8776, LY2603618, V158411, PF-477736, UCN-01, and AZD7762.
EMBODIMENT M-53
[0622] The method as recited in Embodiment M-50, wherein the other therapeutic agent is a DNA-damaging agent.
EMBODIMENT M-54
[0623] The method as recited in Embodiment M-53, wherein the DNA-damaging agent is selected from ionizing radiation, radiomimetic neocarzinostatin, a platinating agent, a Topo I inhibitor, a Topo II inhibitor, an antimetabolite, an alkylating agent, an alkyl sulphonate, and an antibiotic.
EMBODIMENT M-55
[0624] The method as recited in Embodiment M-54, wherein the platinating agent is selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, triplatin tetranitrate, picoplatin, satraplatin, ProLindac, and aroplatin.
EMBODIMENT M-56
[0625] The method as recited in Embodiment M-54, wherein the Topo I inhibitor is selected from camptothecin, topotecan, irinotecan/SN38, rubitecan and belotecan.
EMBODIMENT M-57
[0626] The method as recited in Embodiment M-54, wherein the Topo II inhibitor is selected from etoposide, daunorubicin, doxorubicin, clarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin and teniposide.
EMBODIMENT M-58
[0627] The method as recited in Embodiment M-54, wherein the antimetabolite is selected from aminopterin, methotrexate, pemetrexed, raltitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, and hydroxyurea.
EMBODIMENT M-59
[0628] The method as recited in Embodiment M-54, wherein the alkylating agent is selected from mechlorethamine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine, lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treosulfan, carboquone, thioTEPA, triaziquone, triethylenemelamine, procarbazine, dacarbazine, temozolomide, altretamine, mitobronitol, actinomycin, bleomycin, mitomycin, and plicamycin.
EMBODIMENT M-60
[0629] The method as recited in Embodiment M-38, wherein the method further comprises administering non-chemical methods of cancer treatment.
EMBODIMENT M-61
[0630] The method as recited in Embodiment M-60, wherein the method further comprises administering radiation therapy.
EMBODIMENT M-62
[0631] The method as recited in Embodiment M-60, wherein the method further comprises administering surgery, thermoablation, focused ultrasound therapy, cryotherapy, or any combination thereof.
EMBODIMENT M-63
[0632] A method of increasing the sensitivity of cancer cells to a cancer therapy selected from chemotherapy or radiation therapy by administering to a patient a compound as recited in Embodiment I-1.
EMBODIMENT M-64
[0633] The method as recited in Embodiment M-63, wherein the cancer cells are pancreatic cancer cells.
EMBODIMENT M-65
[0634] A method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a patient, wherein the effect is increased sensitivity to chemotherapic agents.
List of Abbreviations
[0635] Boc=tert-butyloxycarbonyl; BPin=4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; Br.sub.2=bromine; Bu=n-butyl; t-Bu=tert-butyl=2,2-dimethylethyl; C.=Celsius; CBz=carboxybenzyl; CDCl.sub.3=deuterated chloroform; CD.sub.3CN=deuterated acetonitrile; DBN=1,5-Diazabicyclo(4.3.0)non-5-ene; DBU=1,8-diazabicyclo(5.4.0)undec-7-ene; DCM=CH.sub.2Cl.sub.2=dichloromethane; DDTT=3-((dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione; DIPEA=iPr.sub.2NEt=diisopropylethylamine; DMAP=4-Dimethylaminopyridine; DMF=dimethylformamide; DMF-d.sub.7=dimethylformamide-d.sub.7; DMSO=dimethyl sulfoxide; DMSO-d.sub.6=dimethyl sulfoxide-d.sub.6; DMTr=dimethoxytrityl=(4-methoxyphenyl).sub.2(phenyl)methyl; D.sub.2O=deuterated water; dppf=1,1-bis(diphenylphosphino)ferrocene; EA=EtOAc=ethyl acetate; ES+=electrospray positive ionization; ES=electrospray negative ionization; Et=ethyl; EtOH=ethanol; h=hour; H=hydrogen; HCl=hydrogen chloride; HCO.sub.2NH.sub.4=ammonium formate; H.sub.2O=water; HPLC=high pressure liquid chromatography, also known as preparative high performance liquid chromatography; int.=intermediate; iPr=isopropyl=2-propyl; M=molar; mCPBA=m-chloroperbenzoic acid; MeCNCH.sub.3CN=acetonitrile; MeOH=methanol; MHz=megahertz; mL=milliliter; min=minute; MS=mass spectrometry; MsCl=methanesulfonyl chloride; W=microwave; N.sub.2=nitrogen; NH.sub.3=ammonia; NH.sub.4OH=ammonium hydroxide; NMP=N-Methyl-2-pyrrolidone; .sup.1H-NMR=proton nuclear magnetic resonance; .sup.31P-NMR=phosphorous nuclear magnetic resonance; PBS=phosphate buffered saline; PE=petroleum ether; Pin=pinacol=2,3-dimethylbutane-2,3-diol; Pin.sub.2B.sub.2=4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane); Piv=pivaloyl=(CH.sub.3).sub.3CC(O); PPA=polyphosphoric acid; prep-HPLC=preparative high pressure liquid chromatography, also known as preparative high performance liquid chromatography; RT=room temperature; NaOH=sodium hydroxide; Pd(dppf)Cl.sub.2=[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; RuPhos=dicyclohexyl(2,6-diisopropoxy-[1,1-biphenyl]-2-yl)phosphine; THF=tetrahydrofuran; Py=pyridine; SFC=supercritical fluid chromatography; TBSCl=tert-butyldimethylsilyl chloride; TEA=triethylamine; TEAB=tetraethyl ammonium bicarbonate; TMSCl=trimethylsilyl chloride; TFA=trifluoroacetic acid; K.sub.2CO.sub.3=potassium carbonate; L=ul=microliter.
General Synthetic Methods for Preparing Compounds
[0636] The following schemes can be used to practice the present disclosure.
##STR00069##
[0637] A Buchwald coupling reaction with chloro-pyrimidine 101 and a sulfoximine gives the substituted pyrimidine compound 102.
##STR00070##
[0638] One route for preparation of compounds of the present disclosure is depicted in Scheme II. A Buchwald coupling with intermediate 201 and a sulfoximine provides chloropyrimidine 202. A subsequent Suzuki coupling with a boronic ester or a Stille coupling with a stannane affords the pyrimidine compound 203.
##STR00071##
[0639] One route for preparation of compounds of the present disclosure is depicted in Scheme III. A Buchwald coupling with chloropyrimidine 301 and an aryl amine, followed by iron mediated reduction or palladium catalyzed hydrogenation, provides the amino intermediate 303. Subsequent cyclization with either an orthoester or a carboxylic acid affords the pyrimidine compound 304.
##STR00072##
[0640] One route for preparation of compounds of the present disclosure is depicted in Scheme IV. Conversion of chloropyrimidine 401 to stannane 402 and subsequent Stille coupling with an aryl bromide affords the pyrimidine compound 403.
##STR00073##
[0641] One route for preparation of compounds of the present disclosure is depicted in Scheme V. A Buchwald coupling or a S.sub.NAr addition with chloropyrimidine 501 and an amino-heterocycle affords the pyrimidine compound 402.
INTERMEDIATE A
[0642] ##STR00074##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
[0643] ##STR00075##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
[0644] A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 51.0 mmol), Pin.sub.2B.sub.2 (15.5 g, 61.0 mmol), PdCl.sub.2(dppf) (2.0 g, 2.5 mmol) and KOAc (10.0 g, 102 mmol) in 1,4-dioxane (200 mL) was degassed with Ar for 5 minutes. The reaction mixture was heated to 80 C. and stirred for 16 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-25% EtOAc in hexanes) to afford the title compound (3.8 g, 31% yield) as a white solid.
[0645] MS (ES.sup.+) C.sub.13H.sub.17BN.sub.2O.sub.2 requires: 244, found: 245 [M+H].sup.+.
INTERMEDIATE B
[0646] ##STR00076##
(R)-4-(6-chloro-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine
[0647] ##STR00077##
6(R)-4-(2,6-Dichloropyrimidin-4-yl)-3-methylmorpholine
[0648] To a solution of 2,4,6-trichloropyrimidine (12.3 g, 67.3 mmol) and Et.sub.3N (14.2 mL, 101 mmol) in EtOH (80 mL) was added (R)-3-methylmorpholine (6.8 g, 67 mmol). The reaction mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with CH.sub.2Cl.sub.2 (200 mL), partitioned with H.sub.2O (150 mL) and the layers were separated. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3150 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-5% EtOAc in hexanes) to afford the title compound (11.8 g, 71% yield) as a white solid.
[0649] MS (ES.sup.+) C.sub.9H.sub.11Cl.sub.2N.sub.3O requires: 241, found: 248 [M+H].sup.+.
##STR00078##
(R)-4-(6-Chloro-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine
[0650] A mixture of the product from the previous step (3.0 g, 12 mmol), Int. A (2.8 g, 12 mmol), PdCl.sub.2(dppf) (0.44 g, 0.60 mmol) and Na.sub.2CO.sub.3 (2.6 g, 24 mmol) in 1,4-dioxane (60 mL) and water (15 mL) was degassed with Ar for 5 minutes. The reaction mixture was heated to 90 C. and stirred for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (1.84 g, 46% yield) as a yellow solid.
[0651] MS (ES.sup.+) C.sub.16H.sub.16ClN.sub.5O requires: 329, found: 330 [M+H].sup.+.
INTERMEDIATE C
[0652] ##STR00079##
Iminodimethyl-.SUP.6.-sulfanone
[0653] ##STR00080##
Benzyl (dimethyl(oxo)-.SUP.6.-sulfaneylidene)carbamate
[0654] To a suspension of DMSO (780 mg, 10.0 mmol), benzyl carbamate (2.3 g, 15 mmol), Rh.sub.2(OAc).sub.4 (110 mg, 0.25 mmol) and MgO (1.6 g, 40 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added PhI(OAc).sub.2 (4.8 g, 15 mmol). The resulting mixture was stirred at RT for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-90% EtOAc in petroleum ether) to afford the title compound (900 mg, 40% yield) as a white solid.
[0655] MS (ES.sup.+) C.sub.10H.sub.13NO.sub.3S requires: 227, found: 228 [M+H].sup.+.
##STR00081##
Iminodimethyl-.SUP.6.-sulfanone
[0656] The product from the previous step (600 mg, 2.6 mmol) and Pd/C (243 mg, 2.6 mmol) were suspended in MeOH (20 mL). The mixture was stirred under an atmosphere of H.sub.2 at 1 atm for 16 h. The reaction mixture was purged with N.sub.2, filtered through CELITE and the filter pad was washed with MeOH (10 mL). The mixture was concentrated under reduced pressure to afford the title compound (205 mg, 85% yield) as a colorless oil.
[0657] MS (ES.sup.+) C.sub.2H.sub.7NOS requires: 93, found 94 [M+H].sup.+.
INTERMEDIATE D
[0658] ##STR00082##
(R)-((2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0659] ##STR00083##
(R)-((2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0660] A reaction vial was charged with (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described for Int. B, step 1) (500 mg, 2.02 mmol), Int. C (225 mg, 2.42 mmol) and dioxane (10 mL) and the mixture was degassed with N.sub.2 for 30 seconds. Cs.sub.2CO.sub.3 (1.97 g, 6.05 mmol), Pd.sub.2dba.sub.3 (185 mg, 0.202 mmol) and xantphos (233 mg, 0.403 mmol) were added and the mixture was degassed with N.sub.2 for 30 seconds. The vial was sealed and heated at 85 C. for 16 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% MeOH in EtOAc) to afford (R)-((2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.sup.6-sulfanone (362 mg, 59% yield) as a pale yellow solid and (R)-((4-chloro-6-(3-methylmorpholino)pyrimidin-2-yl)imino)dimethyl-.sup.6-sulfanone (222 mg, 36% yield) as a pale yellow solid.
[0661] .sup.1H NMR (600 MHz, CDCl.sub.3) 5.73 (s, 1H), 4.21-4.15 (m, 1H), 3.96 (dd, J=11.5, 3.7 Hz, 1H), 3.91 (d, J=13.0 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H), 3.67 (dd, J=11.5, 3.2 Hz, 1H), 3.52 (td, J=11.9, 3.1 Hz, 1H), 3.37 (d, J=3.1 Hz, 6H), 3.19 (td, J=12.8, 3.9 Hz, 1H), 1.26 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.11H.sub.17ClN.sub.4O.sub.2S requires: 304, found: 305 [M+H].sup.+.
INTERMEDIATE E
[0662] ##STR00084##
Cyclopropyl(imino)(methyl)-.SUP.6.-sulfanone
Step 1
[0663] ##STR00085##
(Methylsulfinyl)cyclopropane
[0664] To a solution of 1-bromo-4-(methylsulfinyl)benzene (10.5 g, 48.0 mmol) in THF (100 mL) was added cyclopropylmagnesium bromide (1M, 72 mL, 72 mmol) at 0 C. slowly. The mixture was stirred at 0 C. for 1.5 h. Saturated aqueous NH.sub.4Cl was added (200 mL), the layers were separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (5150 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (50-100% EtOAc in petroleum ether) to afford the title compound (3.2 g, 64% yield) as a yellow oil.
[0665] MS (ES.sup.+) C.sub.4H.sub.8OS requires: 104, found 105 [M+H].sup.+.
Step 2
[0666] ##STR00086##
Cyclopropyl(imino)(methyl)-.SUP.6.-sulfanone
[0667] To the solution of the product from the previous step (22 g, 0.21 mol) and PhI(OAc).sub.2 (204 g, 0.64 mol) in MeOH (100 mL) at 0 C. was added NH.sub.3 (120 mL, 0.84 mol, 7 N in MeOH) dropwise. The resulting mixture was allowed to warm to RT and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified via flash chromatography (15% EtOAc in petroleum ether, then with 2% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (20 g, 79%) as a yellow oil: .sup.1H NMR (400 MHz, CDCl3) 3.06 (s, 3H), 2.58 (tt, J=7.9, 4.8 Hz, 1H), 1.26-1.19 (m, 1H), 1.19-1.12 (m, 1H), 1.05 (dt, J=11.1, 4.5 Hz, 2H).
INTERMEDIATE F
[0668] ##STR00087##
Imino(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
Step 1
[0669] ##STR00088##
3-(methylsulfinyl)oxetane
[0670] To a solution of 3-iodooxetane (6.0 g, 32.6 mmol) in DMF (60 mL) was added CH.sub.3SNa (2.28 g, 32.6 mmol) under N.sub.2. The reaction mixture was stirred at RT for 1 h. EtOAc (120 mL) and water (80 mL) were added, the layers were separated and the organic layer was washed with brine (80 mL), dried over MgSO.sub.4 and filtered. The solution of EtOAc was added MeOH (60 mL), water (60 mL) and NaIO.sub.4 (6.2 g, 29.3 mmol) and the reaction mixture was stirred at RT for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (50% EtOAc in petroleum ether to 10% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (3.5 g, 90% yield) as pale yellow oil.
[0671] MS (ES.sup.+) C.sub.4H.sub.8O.sub.2S requires: 120, found 121 [M+H].sup.+.
Step 2
[0672] ##STR00089##
Benzyl (methyl(oxetan-3-yl)(oxo)-.SUP.6.-sulfaneylidene)carbamate
[0673] To a solution of the product from the previous step (3.5 g, 29 mmol) in CH.sub.2Cl.sub.2 (260 mL) were added benzyl carbamate (6.58 g, 43.6 mmol), Rh.sub.2(OAc).sub.4 (383 mg, 0.873 mmol), PhI(OAc).sub.2 (14.0 g, 43.6 mmol) and MgO (4.7 g, 116 mmol) and the mixture was stirred at RT under an atmosphere of N.sub.2 for 16 h. The reaction mixture was filtered through CELITE and concentrated under reduced pressure. The residue was purified via flash chromatography (20-50% EtOAc in petroleum ether) to afford the title compound (4.1 g, 52% yield) as pale yellow oil.
[0674] MS (ES.sup.+) C.sub.12H.sub.15NO.sub.4S requires: 269, found 270 [M+H].sup.+.
Step 3
[0675] ##STR00090##
Imino(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
[0676] To a solution of the product from the previous step (4.1 g, 15 mmol) in MeOH (60 mL) was added Pd/C (4.1 g) under N.sub.2. The atmosphere was removed and purged with H.sub.2 (3). The mixture was heated to 50 C. and stirred for 3 h under a H.sub.2 atmosphere. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure to afford the title compound (1.7 g, 83% yield) as pale yellow oil.
[0677] MS (ES.sup.+) C.sub.4H.sub.9NO.sub.2S requires: 135, found 136 [M+H].sup.+.
INTERMEDIATE G
[0678] ##STR00091##
2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine
Step 1
[0679] ##STR00092##
4-Bromo-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine
[0680] To a solution of 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.9 mmol) in THF (30 mL) at 78 C. was added LDA (2.9 mL, 2 M, in THF) and the mixture was stirred for 1 h at 78 C. under an atmosphere of Ar. MeI (4.0 g, 29 mmol) was added and the mixture was allowed to warm to RT and stirred for 3 h. Saturated aqueous NH.sub.4Cl (50 mL) was added and the aqueous layer was extracted with EtOAc (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=65-95%; 18 min; Column: Welch XB-C18, 10 m, 21.2250 mm) to afford the title compound (420 mg, 40% yield) as a white solid.
[0681] MS (ES.sup.+) C.sub.15H.sub.13BrN.sub.2O.sub.2S requires: 364, found 365 [M+H].sup.+.
Step 2
[0682] ##STR00093##
2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine
[0683] A reaction vial was charged with the product from the previous reaction (410 mg, 1.13 mmol), Pin.sub.2B.sub.2 (345 mg, 1.3 mmol), KOAc (277 mg, 2.8 mmol) and Pd(dppf)Cl.sub.2 (82 mg, 0.11 mmol) in dioxane (5 mL). The mixture was degassed by bubbling Ar for 1 min. The mixture was heated at 80 C. and stirred for 5 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. the residue was purified via flash chromatography (20% EtOAc in petroleum ether) to afford the title compound (350 mg, 75% yield) as a white solid.
[0684] MS (ES.sup.+) C.sub.21H.sub.25EN.sub.2O.sub.4S requires 412, found 331 [M81].sup.+.
INTERMEDIATE H
[0685] ##STR00094##
4-Bromo-6-ethoxy-1H-pyrrolo[2,3-b]pyridine
Step 1
[0686] ##STR00095##
4-Bromo-6-ethoxy-1H-pyrrolo[2,3-b]pyridine
[0687] A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (426 mg, 2.0 mmol) and dimethyl sulfate (303 mg, 2.4 mmol) in CH.sub.3CN (10 mL) was heated to 70 C. for 24 h. The reaction mixture was cooled to RT, sodium ethanolate (40 mg, 6.0 mmol) was added and the mixture was heated to 70 C. for 24 h. The reaction mixture was cooled to RT, neutralized with AcOH to pH=7 and then concentrated under reduced pressure. The residue was dissolved in CH.sub.2Cl.sub.2 (50 mL), washed with aq. sat. NaHCO.sub.3 (20 mL) and brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-20% EtOAc in petroleum ether) to afford the title compound (151 mg, 31% yield) as a white solid.
[0688] MS (ES.sup.+) C.sub.9H.sub.9BrN.sub.2O requires: 240, found: 241 [M+H].sup.+.
INTERMEDIATE I
[0689] ##STR00096##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine
Step 1
[0690] ##STR00097##
4-Bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridine
[0691] To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine (300 mg, 1.5 mmol) in DMF (10 mL) at 0 C. was added NaH (92 mg, 2.25 mmol, 60%) and the reaction mixture was stirred at 0 C. for 2 h. The reaction mixture was allowed to warm to RT, TsCl (429 mg, 2.25 mmol) was added and the mixture was heated to 60 C. and stirred for an additional 2 h. H.sub.2O (10 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (315 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-20% EtOAc in petroleum ether) to afford the title compound (300 mg, 57% yield) as a white solid.
[0692] MS (ES.sup.+) C.sub.14H.sub.11BrN.sub.2O.sub.2S requires 350, found 351 [M81].sup.+.
Step 2
[0693] ##STR00098##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine
[0694] A mixture of the product from the previous step (300 mg, 0.86 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (254 mg, 1.0 mmol), Pd(dppf)Cl.sub.2 (63 mg, 0.086 mmol) and KOAc (169 mg, 1.72 mmol) in dioxane (10 mL) was degassed with Ar and the reaction mixture was heated at 120 C. for 4 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by flash chromatography (10-60% EtOAc in petroleum ether) to afford the title compound (100 mg, 29% yield) as a white solid.
[0695] MS (ES.sup.+) C.sub.20H.sub.23BN.sub.2O.sub.4S requires 398, found 399 [M+H].sup.+.
INTERMEDIATE J
[0696] ##STR00099##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2,3-diamine
[0697] ##STR00100##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2,3-diamine
[0698] To a solution of 4-bromopyridine-2,3-diamine (200 mg, 1.07 mmol), KOAc (262 mg, 2.67 mmol) and Pin.sub.2B.sub.2 (544 mg, 2.14 mmol) in dioxane (10 mL) was added Pd(dppf)Cl.sub.2 (63 mg, 0.086 mmol) and the mixture was stirred at 80 C. for 16 h under an atmosphere of Ar. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was taken up in petroleum ether (20 mL) and stirred for 10 minutes, filtered and concentrated to afford the title compound (>250 mg, assumed quantitative) as a brown solid.
[0699] MS (ES.sup.+) C.sub.11H.sub.18BN.sub.3O.sub.2 requires: 235, found 154 [M81].sup.+.
INTERMEDIATE K
[0700] ##STR00101##
6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
[0701] ##STR00102##
6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
[0702] A suspension of 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.432 mmol), Pin.sub.2B.sub.2 (121 mg, 0.475 mmol) and KOAc (127 mg, 1.30 mmol) in dioxane (2160 L) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (17 mg, 0.022 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated to 100 C. and stirred for 12 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure to afford the title compound (assumed quantitative) as a brown solid.
[0703] MS (ES+) C.sub.13H.sub.16BClN.sub.2O.sub.2 requires: 278, found: 279 [M+H].sup.+.
INTERMEDIATE L
[0704] ##STR00103##
N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
[0705] ##STR00104##
N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
[0706] To a solution of 4-bromo-N-methylpyridin-2-amine (85 mg, 0.45 mmol), KOAc (132 mg, 1.35 mmol) and Pin.sub.2B.sub.2 (220 mg, 0.9 mmol) in dioxane (15 mL) was added Pd(dppf)Cl.sub.2 (15 mg, 0.02 mmol) and the mixture was heated at 90 C. and stirred for 16 h under an atmosphere of N.sub.2. The reaction mixture was cooled to RT, EtOAc (50 mL) was added and the mixture was stirred for 5 min. The mixture was filtered through CELITE and concentrated under reduced pressure to give the title compound (100 mg) as a brown solid, which was used without further purification.
[0707] MS (ES.sup.+) C.sub.12H.sub.19BN.sub.2O.sub.2 requires: 234, found: 153 [M81].sup.+.
INTERMEDIATE M
[0708] ##STR00105##
7-Iodo-3-trityl-3H-imidazo[4,5-b]pyridine
Step 1
[0709] ##STR00106##
7-Iodo-3H-imidazo[4,5-b]pyridine hydroiodide
[0710] A mixture of 7-chloro-3H-imidazo[4,5-b]pyridine (735 mg, 4.80 mmol) in aq. HI (12 mL) was heated at 80 C. and stirred for 16 h. The mixture was cooled to RT, the solid was collected by vacuum filtration and dried under vacuum to afford the title compound (1.5 g, 84% yield) as a yellow solid.
[0711] MS (ES.sup.+) C.sub.6H.sub.4IN.sub.3 requires: 245, found: 246 [M+H].sup.+.
Step 2
[0712] ##STR00107##
7-Iodo-3-trityl-3H-imidazo[4,5-b]pyridine
[0713] To a solution of the product from the previous step (735 mg, 1.97 mmol) in DMF (8 mL) at 5 C. was added NaH (158 mg, 3.94 mmol, 60% in mineral oil) and the resulting mixture was stirred at this temperature for 2 h. The the reaction mixture was added a solution of trityl chloride (822 mg, 2.96 mmol) in DMF (2 mL) dropwise and the resulting mixture was stirred an additional 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified via silica gel chromatography (10-25% EtOAc in hexanes) to afford the title compound (620 mg, 65% yield) as a white solid.
[0714] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.23 (s, 1H), 7.71 (d, J=5.0 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.39-7.25 (m, 9H), 7.20 (d, J=7.2 Hz, 6H).
INTERMEDIATE N
[0715] ##STR00108##
(R)-(4-benzylmorpholin-3-yl)methanol
Step 1
[0716] ##STR00109##
Benzoyl-D-serine
[0717] To a stirred solution of (R)-2-amino-3-hydroxypropanoic acid (50 g, 476 mmol), benzoyl chloride (66.64 g, 476 mmol) and K.sub.2CO.sub.3 (131.6 g, 952 mmol) in H.sub.2O (500 mL) at 25 C. for 16 h. The reaction mixture was adjusted to pH=3-4 with 1 N HCl and the aqueous layer was extracted with EtOAc (800 mL). The organic layer was washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (35.8 g, 40% yield) as a white solid.
[0718] MS (ES.sup.+) C.sub.10H.sub.11NO.sub.4 requires: 209, found: 210 [M+H].sup.+.
Step 2
[0719] ##STR00110##
N-benzoyl-O-benzyl-D-serine
[0720] To suspension of NaH (33.06 g, 1378 mmol) in DMF (300 mL) at 0 C. under an atmosphere of N.sub.2 was added the product from the previous step (96 g, 459 mmol) in DMF (300 mL) and the resulting mixture was stirred for 1 h at 0 C. Benzyl bromide (54.54 mL, 459.2 mmol) was added and the mixture was allowed to warm to RT and stirred for 5 h. The reaction mixture was poured into ice water, the layers were separated and the aqueous phase was extracted with Et.sub.2O (1200 mL). The aqueous phase was acidified with 4 N HCl and extracted with CH.sub.2Cl.sub.2 (1200 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (126 g, 69% yield), which was used without further purification.
[0721] MS (ES.sup.+) C.sub.17H.sub.17NO.sub.4 requires: 299, found: 300 [M+H].sup.+.
Step 3
[0722] ##STR00111##
(S)-2-(benzylamino)-3-(benzyloxy)propan-1-ol
[0723] To a solution of the product from the previous step (50 g, 167 mmol) in THF (500 mL) was added BH.sub.3-THF (1 M in THF, 1.8 L, 1672 mmol) at 0 C. under an atmosphere of N.sub.2 and the resulting mixture was warmed to RT and stirred for 16 h. MeOH (1 L) was added dropwise and the mixture was concentrated under reduced pressure. MeOH (1.5 L) and 1 N aq. NaOH (2.225 L) was added to the residue, and the mixture was heated at reflux for 3 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was partitioned between H.sub.2O (2 L) and EtOAc (2 L) and the layers were separated. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (40 g, 88% yield) as colorless oil, which was used without further purification.
[0724] MS (ES.sup.+) C.sub.17H.sub.21NO.sub.2 requires: 271, found: 272 [M+H].sup.+.
Step 4
[0725] ##STR00112##
(R)-4-benzyl-5-((benzyloxy)methyl)morpholin-3-one
[0726] To a solution of the product from the previous step (10 g, 37 mmol) in CH.sub.2Cl.sub.2 (100 mL) at 0 C. was added triethylamine (5.91 mL, 42.4 mmol) and chloroacetyl chloride (3.35 ml, 42.4 mmol) and the resulting mixture was stirred for 1 h at 0 C. The reaction mixture was partitioned between 1N HCl (100 mL) and CH.sub.2CL.sub.2 (100 mL) and the layers were separated. The organic layer was washed with brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was dissolved into 2-propanol (150 mL), KOH (4.14 g, 73.8 mmol) was added and the mixture was stirred for 15 hours at RT. The mixture was concentrated under reduced pressure, the residue was partitioned between water (100 mL) and EtOAc (100 mL) and the layers were separated. The organic layer was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc in hexanes) to afford the title compound (7.46 g, 65% yield) as a yellowish oil.
[0727] MS (ES.sup.+) C.sub.19H.sub.21NO.sub.3 requires: 311, found: 312 [M+H].sup.+.
Step 5
[0728] ##STR00113##
(R)-4-benzyl-5-(hydroxymethyl)morpholin-3-one
[0729] To a suspension of the product from the previous step (25 g, 80 mmol) and 10% palladium on activated carbon (13 g, 8 mmol) in EtOH (150 mL) and acetic acid (50 mL) was stirred at 40 C. under an atmosphere of H.sub.2 at 1 atm for 16 h. The mixture was cooled to RT, purged with N.sub.2, filtered through CELITE and concentrated under reduced pressure. The residue was concentrated from toluene (2100 mL) to afford the title compound (32 g, assumed quantitative), which was used without further purification.
[0730] MS (ES.sup.+) C.sub.12H.sub.15NO.sub.3 requires: 221, found: 222 [M+H].sup.+.
Step 6
[0731] ##STR00114##
(R)-(4-benzylmorpholin-3-yl)methanol
[0732] To a solution of the product from the previous step (24 g, 108.55 mmol) in THF (50 mL) under an atmosphere of N.sub.2 was added borane-methyl sulfide complex (1.0 M in THF, 40 mL) and the resulting was heated at 80 C. for 16 h. The mixture was cooled to RT, MeOH (60 mL) was added dropwise and concentrated under reduced pressure. The residue was partitioned between MeOH (40 mL) and 1 N aq. NaOH (40 mL) and the layers were separated. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% EtOAc in hexanes) to afford the title compound (21.8 g, 97% yield) as a white solid.
[0733] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.37-7.18 (m, 5H), 4.59 (t, J=5.3 Hz, 1H), 4.04 (d, J=13.6 Hz, 1H), 3.79-3.64 (m, 2H), 3.58 (dt, J=11.0, 3.4 Hz, 1H), 3.45-3.35 (m, 3H), 3.27 (d, J=13.6 Hz, 1H), 2.56-2.44 (m, 2H), 2.11 (ddd, J=12.1, 9.1, 3.2 Hz, 1H); MS (ES.sup.+) C.sub.12H.sub.17NO.sub.2 requires: 207, found: 208 [M+H].sup.+.
INTERMEDIATE O
[0734] ##STR00115##
(S)-3-(Fluoromethyl)morpholine
Step 1
[0735] ##STR00116##
(S)-4-benzyl-3-(fluoromethyl)morpholine
[0736] To a solution of Int. N (6.81 g, 3.28 mmol) in CH.sub.2Cl.sub.2 (50 mL) at 0 C. was added diethylaminosulfur trifluoride (6.26 mL, 4.9 mmol) dropwise and the resulting mixture was stirred at RT for 3 h. The reaction mixture was added dropwise to ice-water, aq. sat. NaHCO.sub.3 was added to adjust to pH=8, and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (90% EtOAc in hexanes) to afford the title compound (5.18 g, 70% yield) as a yellow liquid.
[0737] MS (ES.sup.+) C.sub.12H.sub.16FNO requires: 209, found: 210 [M+H].sup.+.
Step 2
[0738] ##STR00117##
(S)-3-(Fluoromethyl)morpholine
[0739] A solution of the product from the previous step (5.18 g, 24.7 mmol) in DCE (50 mL) was added 1-chloroethyl chloroformate (26.7 mL, 247 mmol) and the resulting mixture was heated at 80 C. and stirred for 16 h. The resulting mixture was cooled to RT, MeOH was added until no bubbles were observed, DCE was removed under reduced pressure and the residue was heated at reflux for 1 h. The mixture was cooled to RT, concentrated under pressure and n-heptane was added and the mixture was concentrated under reduced pressure (250 mL). The residue was triturated with EtOAc to afford the title compound (25 g, 60% yield) as a white solid.
[0740] MS (ES.sup.+) C.sub.5H.sub.10FNO requires: 119, found: 120 [M+H].sup.+.
INTERMEDIATE P
[0741] ##STR00118##
5-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
Step 1
[0742] ##STR00119##
5-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
[0743] A sealed tube charged with 4-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.465 mmol), KOAc (137 mg, 1.40 mmol), Pin.sub.2B.sub.2 (142 mg, 0.558 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (19 mg, 0.023 mmol) followed by dioxane (3.1 mL). The mixture was degassed by bubbling with stream of N.sub.2 for 1 minute. The tube was sealed and the reaction mixture was heated for at 90 C. for 18 h. The reaction mixture was cooled to RT, filtered through CELITE, washed with EtOAc (5 mL), and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (112 mg, 46% yield) as a pale yellow solid.
[0744] MS (ES.sup.+) C.sub.13H.sub.16BFN.sub.2O.sub.2 requires: 262, found: 181 [M81].sup.+.
INTERMEDIATE Q
[0745] ##STR00120##
((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[0746] ##STR00121##
((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[0747] To the mixture of Int. E (47 g, 0.19 mol), (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described for Int. B, step 1) (22 g, 0.19 mol) in dioxane (750 mL) were added Pd.sub.2(dba).sub.3 (8.6 g, 9.4 mmol), XantPhos (5.5 g, 9.4 mmol) and Cs.sub.2CO.sub.3 (184 g, 0.57 mol). The reaction mixture was degassed with N.sub.2 for 1 minute and heated to 80 C. and stirred under an atmosphere of N.sub.2 for 6 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-100% EtOAc in hexanes) to afford the title compound (26 g, 41% yield) as an off-white solid.
[0748] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 5.86 (s, 1H), 4.22 (d, J=5.3 Hz, 1H), 3.92-3.80 (m, 2H), 3.66 (d, J=11.4 Hz, 1H), 3.54 (dd, J=11.5, 2.9 Hz, 1H), 3.45 (s, 3H), 3.39 (td, J=11.9, 3.0 Hz, 1H), 3.12-2.93 (m, 2H), 1.26-1.19 (m, 1H), 1.17-1.04 (m, 6H). MS (ES.sup.+) C.sub.13H.sub.19ClN.sub.4O.sub.2S requires: 330, found: 331 [M+H].sup.+.
INTERMEDIATE R
[0749] ##STR00122##
Tert-butyl 1-imino-1.SUP.6.-thiomorpholine-4-carboxylate 1-oxide
Step 1
[0750] ##STR00123##
tert-Butyl 1-(((benzyloxy)carbonyl)imino)-1.SUP.6.-thiomorphohne-4-carboxylate 1-oxide
[0751] To a suspension of tert-butyl thiomorpholine-4-carboxylate 1-oxide (2.0 g, 9.1 mmol), benzyl carbamate (2.10 g, 13.7 mmol), MgO (1.5 g, 36 mmol) and Rh.sub.2(OAc).sub.4 (0.1 g, 0.23 mmol) in CH.sub.2Cl.sub.2 (20 mL) was added PhI(OAc).sub.2 (4.40 g, 13.7 mmol) and the resulting mixture was stirred at RT for 18 h. The reaction mixture was filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-40% EtOAc in petroleum ether) to afford the title compound (2.4 g, 36% yield) as a white solid.
[0752] MS (ES.sup.+) C.sub.17H.sub.24N.sub.2O.sub.5S requires: 368, found: 369 [M+H].sup.+.
Step 2
[0753] ##STR00124##
tert-Butyl 1-imino-1.SUP.6.-thiomorphohne-4-carboxylate 1-oxide
[0754] A suspension of the product from the previous step (1.0 g, 2.7 mmol) and 10% Pd/C (250 mg, 0.235 mmol) in MeOH (20 mL) was stirred under H.sub.2 for 16 h. The reaction mixture was filtered through CELITE and concentrated under reduced pressure to afford the title compound (500 mg, 79% yield) as colorless oil. The crude product was used for subsequent step without further purification.
[0755] MS (ES.sup.+) C.sub.9H.sub.18N.sub.2O.sub.3S requires: 234, found: 235 [M+H].sup.+.
INTERMEDIATE S
[0756] ##STR00125##
6-Methoxy-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine
Step 1
[0757] ##STR00126##
6-Chloro-4-iodo-N-(4-methoxybenzyl)pyridin-2-amine
[0758] A microwave vial was charged with 2,6-dichloro-4-iodopyridine (10 g, 36 mmol), 4-methoxybenzylamine (23.4 mL, 179 mmol) and ethanol (20 mL). The vial was sealed and the reaction mixture was heated to 150 C. in a microwave reactor for 4 h. The mixture was cooled to RT, poured into water (20 mL) and the aqueous layer was extracted with EtOAc (320 mL). The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-20% EtOAc in hexanes) to afford the title compound (9.24 g, 69% yield) as a white solid.
[0759] MS (ES.sup.+) C.sub.13H.sub.12ClIN.sub.2O requires: 374, found: 375 [M+H].sup.+.
Step 2
[0760] ##STR00127##
4-Iodo-6-methoxy-N-(4-methoxybenzyl)pyridin-2-amine
[0761] To a suspension of the product from the previous step (1.0 g, 2.67 mmol) in dioxane (5.3 mL) at 0 C. was added sodium methoxide (1.8 mL, 8.0 mmol, 25% in MeOH) and the resulting mixture was stirred at 100 C. for 16 h. 1 N HCl (5 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (330 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO.sub.4, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-20% EtOAc in hexanes) to afford the title compound (844 mg, 85% yield) as a colorless liquid.
[0762] MS (ES.sup.+) C.sub.14H.sub.15IN.sub.2O.sub.2 requires: 370, found: 371 [M+H].sup.+.
Step 3
[0763] ##STR00128##
6-Methoxy-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
[0764] A suspension of the product from the previous step (900 mg, 2.43 mmol), Pin.sub.2B.sub.2 (741 mg, 2.92 mmol) and KOAc (716 mg, 7.29 mmol) in dioxane (12.2 mL) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (99 mg, 0.12 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated at 120 C. in a microwave reactor for 10 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-60% EtOAc in hexanes) to afford the title compound (860 mg, 72% yield) as a pale yellow liquid.
[0765] MS (ES.sup.+) C.sub.20H.sub.27BN.sub.2O.sub.4 requires: 370, found: 289 [M81].sup.+.
INTERMEDIATE T
[0766] ##STR00129##
(R)-4-(6-chloro-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine
[0767] ##STR00130##
(R)-4-(6-chloro-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine
[0768] To a solution of (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described for Int. B, step 1) (467 mg, 1.88 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (900 mg, 2.26 mmol) in dioxane (7.1 mL) and water (2.4 L) were added Na.sub.2CO.sub.3 (439 mg, 4.14 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (77 mg, 0.094 mmol) and the resulting mixture was degassed with N.sub.2 for 1 minute and stirred at 110 C. for 4 h. The reaction mixture was cooled to RT, partitioned between EtOAc (5 mL) and H.sub.2O (2 mL), the layers were separated and the aqueous layer was extracted with EtOAc (35 mL). The combined organic layers were washed with brine (2 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-60% EtOAc in hexanes) to afford the title compound (300 mg, 33% yield) as an off-white solid.
[0769] .sup.1H NMR (600 MHz, CDCl.sub.3) 8.52 (d, J=5.3 Hz, 1H), 8.06 (t, J=7.1 Hz, 3H), 7.83 (d, J=4.0 Hz, 1H), 7.48 (d, J=3.9 Hz, 1H), 7.26 (d, J=1.5 Hz, 2H), 6.46 (s, 1H), 4.40 (s, 1H), 4.07 (dd, J=11.4, 3.5 Hz, 2H), 3.85 (d, J=11.6 Hz, 1H), 3.75 (dd, J=11.7, 3.1 Hz, 1H), 3.60 (td, J=11.9, 2.8 Hz, 1H), 3.37 (td, J=12.8, 4.0 Hz, 1H), 2.36 (s, 3H), 1.37 (d, J=6.9 Hz, 3H); MS (ES.sup.+) C.sub.23H.sub.22ClN.sub.5O.sub.3S: 483, found: 484 [M+H].sup.+.
INTERMEDIATE U
[0770] ##STR00131##
4-Bromo-2-cyclopropyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine
[0771] ##STR00132##
4-Bromo-2-cyclopropyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine
[0772] A mixture of 4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.3 g, 0.63 mmol), cyclopropylboronic acid (0.054 g, 0.63 mmol), Pd(PPh.sub.3).sub.4 (73 mg, 0.063 mmol), Na.sub.2CO.sub.3 (134 mg, 1.26 mmol), dioxane (10 mL) and H.sub.2O (2 mL) was purged with Are, sealed and heated at 130 C. for 3 h in a microwave reactor. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% EtOAc in hexanes) to afford the title compound (30 mg, 12% yield) as a white solid.
[0773] MS (ES.sup.+) C.sub.17H.sub.15BrN.sub.2O.sub.2S requires: 390 found: 391 [M+H].sup.+.
INTERMEDIATE V
[0774] ##STR00133##
(R)-dimethyl((6-(3-methylmorpholino)-2-(tributylstannyl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0775] ##STR00134##
[0776] (R)-dimethyl((6-(3-methylmorpholino)-2-(tributylstannyl)pyrimidin-4-yl)imino)-.sup.6-sulfanone, intermediate 5: To a flame dried round bottom flask, under an atmosphere of Ar, was added anhydrous THF (2 mL) and di-isopropylamine (310 L, 2.2 mmol). The solution was cooled to 10 C. and n-BuLi (2.5 M in hexanes, 0.84 mL, 2.1 mmol) was added dropwise and the resulting mixture was warmed to 0 C. over 5 minutes. A solution of Bu.sub.3SnH (538 L, 2.0 mmol) in THF (2.0 mL) was added dropwise and the resulting mixture was stirred at 0 C. for 20 minutes, and then cooled to 78 C. A solution of Int. D (610 mg, 2.0 mmol) in THF (2.0 mL) was added to the mixture at 78 C. and the resulting mixture was stirred at 78 C. for 1 h. Water (10 ml) was added to the mixture, the layers were separated and the aqueous layer was extracted with EtOAc (35 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (20 to 100% EtOAc in hexanes) to afford the title compound (350 mg, 31% yield) as a colorless oil.
[0777] MS (ES.sup.+) C.sub.23H.sub.44N.sub.4O.sub.2SSn requires: 560, found: 561 [M+H].sup.+.
INTERMEDIATE W
[0778] ##STR00135##
(S)-3-(difluoromethyl)morpholine hydrochloride
Step 1
[0779] ##STR00136##
(S)-4-benzylmorpholine-3-carbaldehyde
[0780] To a solution of DMSO (20.6 mL, 290 mmol) in CH.sub.2Cl.sub.2 (100 mL) at 78 C. was added a solution of oxalyl chloride (12.2 mL, 145 mmol) in CH.sub.2Cl.sub.2 (50 mL) dropwise and the resulting mixture was stirred was at 78 C. for 15 minutes. A solution of Int. N (10 g, 48 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added over 30 min. and the resulting mixture was warmed to RT and stirred for 30 min. To the reaction mixture was added sat. aq. NaHCO.sub.3 (200 mL) and the layers were separated. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (9.9 g, 99% yield), which was used immediately without further purification.
[0781] MS (ES.sup.+) C.sub.12H.sub.15NO.sub.2 requires: 205 found: 206 [M+H].sup.+.
Step 2
[0782] ##STR00137##
(S)-4-benzyl-3-(difluoromethyl)morpholine
[0783] To a solution of the product from the previous step (9.9 g, 48.267 mmol) in CH.sub.2Cl.sub.2 (100 mL) at 0 C. was added DAST (19.14 mL, 44.8 mmol) was added dropwise while maintaining a temperature of 0-5 C. and the resulting reaction mixture was warmed to RT and stirred for 16 hours. To the reaction mixture was added sat. aq. NaHCO.sub.3 (50 mL) and the layers were separated. The organic layer was washed with water (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes) to afford the title compound (5 g, 45.45% yield) as a yellowish oil.
[0784] MS (ES.sup.+) C.sub.12H.sub.15F.sub.2NO requires: 227 found: 228 [M+H].sup.+.
Step 3
[0785] ##STR00138##
(S)-3-(difluoromethyl)morpholine hydrochloride
[0786] To a solution of the product from the previous step (2.0 g, 8.806 mmol) in DCE (10 mL) was added 1-chloroethyl cloroformate (9.44 mL, 88.1 mmol) and the resulting mixture was heated at 80 C. and stirred for 16 h. The resulting mixture was cooled to RT, MeOH was added until no bubbles were observed, DCE was removed under reduced pressure and the residue was heated at reflux for 1 h. The mixture was cooled to RT, concentrated under pressure and 2-propanol was added and the mixture was concentrated under reduced pressure (210 mL). The residue was triturated with EtOAc to afford the title compound (1.9 g, quantitative yield) as a white solid.
[0787] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 6.42 (td, J=53.7, 3.9 Hz, 1H), 4.04 (dd, J=12.3, 3.5 Hz, 1H), 4.00-3.83 (m, 2H), 3.82-3.60 (m, 2H), 3.25 (dt, J=12.9, 2.7 Hz, 1H), 3.20-3.06 (m, 1H); MS (ES.sup.+) C.sub.5H.sub.9F.sub.2NO requires: 137 found: 138 [M+H].sup.+.
INTERMEDIATE X
[0788] ##STR00139##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole
[0789] ##STR00140##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole
[0790] A mixture of 4-bromo-1H-benzo[d]imidazole (0.5 g, 2.5 mmol), Pin.sub.2B.sub.2 (0.77 g, 3.1 mmol), PdCl.sub.2(dppf) (93 mg, 0.13 mmol) and KOAc (0.5 g, 5.1 mmol) in dioxane (20 mL) was degassed with N.sub.2 for 1 min. and the resulting mixture was heated at 90 C. and stirred for 16 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure to afford the title compound (0.6 g, assumed quantitative) as a black solid, which was directly used for the next step without further purification.
[0791] MS (ES.sup.+) C.sub.13H.sub.17BN.sub.2O.sub.2 requires: 244 found: 163 [M81].sup.+.
INTERMEDIATE Y
[0792] ##STR00141##
6-Chloro-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine
[0793] ##STR00142##
6-Chloro-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
[0794] A sealed tube was charged with 6-chloro-4-iodo-N-(4-methoxybenzyl)pyridin-2-amine (synthesized as described for Int. S, step 1) (500 mg, 1.24 mmol), KOAc (365 mg, 3.72 mmol), Pin.sub.2B.sub.2 (378 mg, 1.49 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.051 g, 0.062 mmol) and dioxane (8.28 mL) and the resulting mixture was degassed with N.sub.2 for 1 minute. The reaction tube was sealed and the reaction mixture was heated at 90 C. for 18 h. The reaction mixture was cooled to RT, filtered through CELITE, washed with EtOAc and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (525 mg, 56% yield) as an orange liquid.
[0795] MS (ES.sup.+) C.sub.19H.sub.24BClN.sub.2O.sub.3 requires: 374, found: 293 [M81].sup.+.
INTERMEDIATE Z
[0796] ##STR00143##
4-Bromo-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3-b]pyridine
[0797] ##STR00144##
4-Bromo-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3-b]pyridine
[0798] A solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.73 g, 8.13 mmol) and dimethyl sulfate (1.23 g, 9.75 mmol) in CH.sub.3CN (50 mL) was heated to 70 C. for 24 h. The reaction mixture was cooled to RT. To a suspension of mixture of NaH (6.24 g, 156 mmol, 60% in mineral oil) in CH.sub.3CN (50 mL) at 0 C. was added 2,2,2-trifluoroethanol (5.2 g, 52 mmol) and the resulting mixture was stirred at 0 C. for 30 minutes. The reaction mixture was then added to the mixture prepared above and the resulting mixture was stirred at 70 C. for 16 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-67% EtOAc in petroleum ether; then 0-40% acetone in petroleum ether) to afford the title compound (450 mg, 19% yield) as a white solid.
[0799] MS (ES.sup.+) C.sub.9H.sub.6BrF.sub.3N.sub.2O requires: 294, 296, found: 295, 297[M+H].sup.+.
INTERMEDIATE AA
[0800] ##STR00145##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]-pyridine-2-carbonitrile
Step 1
[0801] ##STR00146##
4-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile
[0802] A microwave vial was charged with 4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.42 mmol), Zn(CN).sub.2 (24 mg, 0.21 mmol), Pd(PPh.sub.3).sub.4 (24 mg, 0.021 mmol) and DMF (5 mL). The vial was sealed and the reaction mixture was heated at 150 C. in a microwave reactor for 30 minutes. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=50-80%; 18 min; Column: Welch XB-C18, 10 m, 21.2250 mm) to afford the title compound (20 mg, 12% yield) as a white solid.
[0803] MS (ES.sup.+) C.sub.15H.sub.10BrN.sub.3O.sub.2S requires: 375, found: 376 [M+H].sup.+.
Step 2
[0804] ##STR00147##
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile
[0805] A sealed tube was charged with 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile (25 mg, 0.066 mmol), KOAc (19.6 mg, 0.199 mmol), bis(pinacolato)diboron (20.3 mg, 0.0800 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (2.7 mg, 3.3 mol) and dioxane (443 L). The reaction mixture was degassed with N.sub.2 for 30 seconds, sealed and heated at 90 C. for 18 h. The reaction mixture was cooled to RT, filtered through CELITE, washed with EtOAc and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-80% EtOAc in hexanes) to afford the title compound (11 mg, 20% yield) as a pale yellow liquid.
[0806] MS (ES.sup.+) C.sub.21H.sub.22BN.sub.3O.sub.4S requires: 423, found: 342 [M81].sup.+.
INTERMEDIATE BB
[0807] ##STR00148##
Methyl (R)-6-(tert-butylamino)-4-(4-((dimethyhoxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinate
Step 1
[0808] ##STR00149##
Methyl 6-(tert-butylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-picolinate
[0809] A suspension of methyl 4-bromo-6-(tert-butylamino)picolinate (222 mg, 0.773 mmol), Pin.sub.2B.sub.2 (216 mg, 0.850 mmol) and KOAc (228 mg, 2.32 mmol) in dioxane (3.87 mL) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (31.6 mg, 0.039 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated to 100 C. and stirred for 12 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-20% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (226 mg, 87% yield) as a brown liquid.
[0810] MS (ES.sup.+) C.sub.17H.sub.27BN.sub.2O.sub.4 requires: 334, found: 253 [M81].sup.+.
Step 2
[0811] ##STR00150##
Methyl (R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinate
[0812] A suspension of Int. D (81 mg, 0.264 mmol), the product from the previous step (200 mg, 0.599 mmol) and K.sub.2CO.sub.3 (73 mg, 0.53 mmol) in THF (1.2 mL) and water (120 L) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (11 mg, 0.013 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated to 60 C. and stirred for 2 h. The mixture was cooled to RT and the layers were separated. The aqueous layer was extracted with EtOAc (31 mL). The combined organic layers were washed with brine (1 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-60% EtOAc in hexanes) to afford the title compound (150 mg, quantitative yield) as a pale yellow liquid.
[0813] MS (ES.sup.+) C.sub.22H.sub.32N.sub.6O.sub.4S requires: 476, found: 477 [M+H].sup.+.
INTERMEDIATE CC
[0814] ##STR00151##
(R)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone and
[0815] ##STR00152##
(S)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[0816] ##STR00153##
(R)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)-(methyl)-.SUP.6.-sulfanone and (S)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[0817] To solution of Int. E (47 g, 0.19 mol) and (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described for Int. B, step 1) (22 g, 0.19 mol) in dioxane (750 mL) were added Pd.sub.2(dba).sub.3 (8.6 g, 9.4 mmol), XantPhos (5.5 g, 9.4 mmol) and Cs.sub.2CO.sub.3 (184 g, 0.57 mol) and the resulting mixture was purged with N.sub.2 (3), heated to 80 C. and stirred under an atmosphere of N.sub.2 for 6 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-100% EtOAc in hexanes) to afford the title compounds as a mixture of two diastereomers of unknown absolute stereochemistry at the sulfur atom (26 g, 41% yield) as an off-white solid.
[0818] A solution of the mixture of diastereomers (35 g, 0.11 mol) in CH.sub.2Cl.sub.2 (300 mL) was separated by Chiral SFC (Mobile phase: CO.sub.2/EtOH=75/25; Flow rate: 70 g/min; 4 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK AD, 10 m, 20 mm250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom Isomer 1a (15.0 g, 86%) as a light yellow solid and Isomer 1b (14.2 g, 81%) as a light yellow solid.
[0819] Isomer 1a ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (400 MHz, CDCl.sub.3) 5.69 (s, 1H), 4.15-4.05 (m, 1H), 3.93-3.79 (m, 2H), 3.67 (d, J=11.5 Hz, 1H), 3.59 (app. d, J=11.5 Hz, 1H), 3.51-3.39 (m, 1H), 3.36 (s, 3H), 3.12 (td, J=12.8, 3.4 Hz, 1H), 2.87-2.76 (m, 1H), 1.51-1.40 (m, 1H), 1.28-1.21 (m, 1H), 1.19 (d, J=6.7 Hz, 3H), 1.14-0.99 (m, 2H); MS (ES.sup.+) C.sub.13H.sub.19ClN.sub.4O.sub.2S requires: 330, found: 331 [M+H].sup.+; R.sub.t=3.19 min.
[0820] Isomer 1b ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (400 MHz, CDCl.sub.3) 5.68 (s, 1H), 4.14-4.05 (m, 1H), 3.88 (dd, J=11.5, 3.9 Hz, 1H), 3.83 (d, J=13.6 Hz, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.59 (dd, J=11.5, 3.2 Hz, 1H), 3.45 (td, J=11.9, 3.1 Hz, 1H), 3.37 (s, 3H), 3.12 (td, J=12.8, 3.9 Hz, 1H), 2.81 (ddd, J=12.8, 8.0, 4.8 Hz, 1H), 1.49-1.41 (m, 1H), 1.27-1.20 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.14-1.01 (m, 2H); MS (ES.sup.+) C.sub.13H.sub.19ClN.sub.4O.sub.2S requires: 330, found: 331 [M+H].sup.+; R.sub.t=5.62 min.
INTERMEDIATE DD
[0821] ##STR00154##
Imino(methyl)(pyridin-3-yl)-.SUP.6.-sulfanone
[0822] ##STR00155##
Imino(methyl)(pyridin-3-yl)-.SUP.6.-sulfanone
[0823] To a solution of 3-(methylthio)pyridine (1.09 g, 8.72 mmol) in MeOH (10 mL) were added NH.sub.2COONH.sub.4 (1.7 g, 21.8 mmol) and PhI(OAc).sub.2 (7.02 g, 21.8 mmol) and the resulting mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B=MeCN; Gradient: B=95%; 13 min; 30 mL/min; column: Xtimate Prep C18 OBD 21.2250 mm, 10 m) to afford the title compound (760 mg, 55%) as an off-white solid.
[0824] (ES.sup.+) C.sub.6H.sub.8N.sub.2OS requires: 156, found: 157 [M+H].sup.+.
INTERMEDIATE EE
[0825] ##STR00156##
Imino(methyl)(1-methyl-1H-pyrazol-4-yl)-.SUP.6.-sulfanone
Step 1
[0826] ##STR00157##
1-Methyl-4-(methylthio)-1H-pyrazole
[0827] To a solution of 4-iodo-1-methyl-1H-pyrazole (0.5 mL, 5.2 mmol) in THF (2 mL) at 78 C. under an atmosphere of N.sub.2 was added isopropylmagnesium chloride (5.2 mL, 10.4 mmol) and the resulting mixture was stirred for 30 minutes. To the reaction mixture was added dimethyl disulfide (1 mL, 11 mmol). The reaction was poured into aq. sat. NH.sub.4Cl (25 mL), the layers were separated and the aqueous layer was extracted with Et.sub.2O (100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B=MeCN; Gradient: B=95%; 13 min; 30 mL/min; column: Xtimate Prep C18 OBD 21.2250 mm, 10 m) to afford the title compound (740 mg, 29%) as an off-white solid.
[0828] (ES.sup.+) C.sub.5H.sub.8N.sub.2S requires: 128, found: 129 [M+H].sup.+.
Step 2
[0829] ##STR00158##
Imino(methyl)(1-methyl-1H-pyrazol-4-yl)-.SUP.6.-sulfanone
[0830] To solution of the product from the previous step (1.09 g, 8.72 mmol) in MeOH (10 mL) were added NH.sub.2COONH.sub.4 (1.7 g, 21.8 mmol) and PhI(OAc).sub.2 (7.02 g, 21.8 mmol) and the resulting mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B=MeCN; Gradient: B=95%; 13 min; 30 mL/min; column: Xtimate Prep C18 OBD 21.2250 mm, 10 m) to afford the title compound (730 mg, 53%) as an off-white solid.
[0831] (ES.sup.+) C.sub.5H.sub.9N.sub.3OS requires: 159, found: 160 [M+H].sup.+.
INTERMEDIATE FF
[0832] ##STR00159##
2-(((Triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazole
[0833] ##STR00160##
2-(((Triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazole
[0834] To a solution of (1H-benzo[d]imidazol-2-yl)methanol (1.66 g, 11.2 mmol), imidazole (0.92 g, 13 mmol) and DMAP (0.068 g, 0.56 mmol) in DMF (10 mL) was added neat TIPSCl (2.87 mL, 13.4 mmol) and the resulting mixture was stirred at RT for 48 h. The reaction mixture was poured into water (100 mL), the layers were separated and the aqueous layer was extracted with Et.sub.2O (2100 mL). The combined organic layers were washed with water (2100 mL) followed by brine (100 mL), stirred over MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (3.40 g, 99% yield) as a white solid.
[0835] MS (ES.sup.+) C.sub.17H.sub.28N.sub.2OSi requires: 304 found: 305 [M+H].sup.+.
EXAMPLE 1
[0836] ##STR00161##
(R)-dimethyl ((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0837] ##STR00162##
(R)-dimethyl(6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0838] A reaction vial was charged with Int. B (100 mg, 0.30 mmol), Int. C (34 mg, 0.36 mmol), RuPhos Pd G4 (26 mg, 0.030 mmol), RuPhos (14 mg, 0.030 mmol), Cs.sub.2CO.sub.3 (293 mg, 0.90 mmol) and 1,4-dioxane (2 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was stirred at 85 C. for 16 h. The reaction mixture was cooled to RT, filtered through CELITE, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 M NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=20-50%; 10 min; Column: Venusil ASB C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (33.0 mg, 28% yield) as a white solid.
[0839] .sup.1H NMR (500 MHz, DMSO) 11.72 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.89 (d, J=5.0 Hz, 1H), 7.59-7.49 (m, 1H), 7.41 (dd, J=3.3, 1.9 Hz, 1H), 5.92 (s, 1H), 4.45 (s, 1H), 4.06 (d, J=12.8 Hz, 1H), 3.96 (dd, J=11.3, 3.4 Hz, 1H), 3.75 (d, J=11.3 Hz, 1H), 3.64 (dd, J=11.3, 2.9 Hz, 1H), 3.53-3.47 (m, 1H), 3.45 (s, 6H), 3.15 (td, J=12.8, 3.8 Hz, 1H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.22N.sub.6O.sub.2S requires: 386, found: 387 [M+H].sup.+.
[0840] The compounds reported in Table 2 were synthesized using the method described for the previously disclosed Examples. The appropriate sulfoximines were prepared as described for Intermediates C.
TABLE-US-00001 TABLE 1 Example compounds 2-9 Ex. Ex Structure IUPAC Name MWt [M + H] Method 2
EXAMPLE 10
[0841] ##STR00171##
(R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
Step 1
[0842] ##STR00172##
(R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0843] A solution of Int. D (45 mg, 0.148 mmol), Int. P (101 mg, 0.192 mmol) and K.sub.2CO.sub.3 (51 mg, 0.37 mmol) in dioxane (671 L) and water (67 L) was degassed with a stream of N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (6.0 mg, 7.9 mol) was added, the mixture was degassed with a stream of N.sub.2 for an additional 1 minute, and the reaction mixture was heated at 85 C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE, washed with CH.sub.2Cl.sub.2 (2 mL) and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (32 mg, 34% yield) as a pale yellow solid.
[0844] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 8.31 (d, J=3.0 Hz, 1H), 7.66 (d, J=3.4 Hz, 1H), 6.71 (d, J=3.5 Hz, 1H), 6.31 (s, 1H), 4.63 (s, 1H), 4.19 (s, 1H), 4.04 (dd, J=11.9, 3.8 Hz, 1H), 3.83 (d, J=11.8 Hz, 1H), 3.75 (dd, J=11.9, 3.2 Hz, 1H), 3.61 (td, J=11.9, 2.9 Hz, 1H), 3.57 (d, J=5.4 Hz, 6H), 3.51 (t, J=13.5 Hz, 1H), 1.42 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.21FN.sub.6O.sub.2S requires: 404, found: 405 [M+H].sup.+.
EXAMPLE 11
[0845] ##STR00173##
(R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
Step 1
[0846] ##STR00174##
(R)-dimethyl((2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0847] A reaction vial was charged with Int. D (103 mg, 0.5 mmol), Int. G (280 mg, 0.68 mmol), Na.sub.2CO.sub.3 (216 mg, 2.04 mmol), PdCl.sub.2(dppf) (25 mg, 0.034 mmol), dioxane (3 mL) and H.sub.2O (1 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was stirred at 80 C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc in hexanes) to afford the title compound (50 mg, 26% yield) as a white solid.
[0848] MS (ES.sup.+) C.sub.26H.sub.30N.sub.6O.sub.4S.sub.2 requires: 554, found: 555 [M+H].sup.+.
Step 2
[0849] ##STR00175##
(R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0850] A mixture of the product from the previous step (50 mg, 0.09 mmol), NaOH (72 mg, 1.8 mmol), H.sub.2O (1 mL) and MeOH (2 mL) was stirred at 70 C. for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. MeOH (30 mL) was added, the mixture was stirred for 5 min, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=30-60%; 18 min; Column: Welch XB-C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (15 mg, 41% yield) as a white solid.
[0851] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.53 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.81 (d, J=4.8 Hz 1H), 7.11 (s, 1H), 5.89 (s, 1H), 4.44 (s, 1H), 4.04 (s, 1H), 3.95 (s, 1H), 3.75 (d, J=12.6 Hz, 1H), 3.65 (s, 1H), 3.47 (d, J=19.4 Hz, 7H), 3.14 (s, 1H), 2.42 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.
EXAMPLE 12
[0852] ##STR00176##
(R)-1-(1-((6-(3-Methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxido-1.SUP.6.-thiomorpholino)ethan-1-one
Step 1
[0853] ##STR00177##
Tert-butyl (R)-1-((6-(3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1.SUP.6.-thiomorpholine-4-carboxylate 1-oxide
[0854] A mixture Int. R (145 mg, 0.62 mmol), Int. T (300 mg, 0.62 mmol), Pd.sub.2(dba).sub.3 (57 mg, 0.062 mmol), X-phos (30 mg, 0.062 mmol) and Cs.sub.2CO.sub.3 (407 mg, 1.24 mmol) in dioxane (10 mL) was degassed with Ar for 5 minutes. The reaction mixture was heated to 100 C. and stirred for 3 h. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (310 mg, 73% yield) as a yellow solid.
[0855] MS (ES.sup.+) C.sub.32H.sub.39N.sub.7O.sub.6S.sub.2 requires: 681, found: 682 [M+H].sup.+.
Step 2
[0856] ##STR00178##
(R)-1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1.SUP.6.-thiomorpholine 1-oxide
[0857] A mixture of the product from the previous step (300 mg, 0.44 mmol), TFA (1 mL) and CH.sub.2Cl.sub.2 (5 mL) was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to give a yellow oil. MeOH (5 mL) and NaOH (18 mg, 0.88 mmol) were added and the mixture was stirred at 60 C. for 1 h. The mixture was cooled to RT, H.sub.2O (10 mL) was added and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (315 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (150 mg, 80% yield) as a white solid.
[0858] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 1 1.78 (s, 1H), 9.03 (s, 1H), 8.31 (d, J=5.1 Hz, 1H), 7.86 (d, J=5.0 Hz, 1H), 7.57 (s, 1H), 7.33 (s, 1H), 6.07 (s, 1H), 4.50 (s, 1H), 3.98 (d, J=1 1.4 Hz, 6H), 3.87-3.82 (m, 3H), 3.52 (s, 4H), 3.19 (s, 1H), 1.23 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.20H.sub.25N.sub.7O.sub.2S requires: 427, found: 428 [M+H].sup.+.
Step 3
[0859] ##STR00179##
(R)-1-(1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxido-1.SUP.6.-thiomorpholino)ethan-1-one
[0860] To a solution of the product from the previous step (100 mg, 0.23 mmol) and Et.sub.3N (0.5 mL, 0.5 mmol) in CH.sub.2Cl.sub.2 (5 mL) at 0 C. was added acetyl chloride (18 mg, 0.23 mmol) and the resulting mixture was warmed to RT and stirred for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=25-55%; 15 min; Column: Welch XB-C18, 10 m, 21.2250 mm) to afford the title compound (36 mg, 33% yield) as a white solid.
[0861] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.86 (d, J=5.0 Hz, 1H), 7.59-7.50 (m, 1H), 7.37 (dd, J=3.2, 2.0 Hz, 1H), 6.02 (s, 1H), 4.49 (s, 1H), 4.18 (s, 1H), 4.11-3.82 (m, 4H), 3.79-3.56 (m, 6H), 3.53-3.39 (m, 2H), 3.17 (s, 1H), 2.07 (d, J=2.0 Hz, 3H), 1.22 (d, J=6.6 Hz, 3H); MS (ES.sup.+) C.sub.22H.sub.27N.sub.7O.sub.3S requires: 469, found: 470 [M+H].sup.+.
EXAMPLE 13
[0862] ##STR00180##
(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
Step 1
[0863] ##STR00181##
[0864] (R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.sup.6-sulfanone
[0865] A solution of Int. D (150 mg, 0.492 mmol), Int. Y (516 mg, 0.689 mmol) and K.sub.2CO.sub.3 (170 mg, 1.23 mmol) in dioxane (2.2 mL) and water (224 L) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2A (20.1 mg, 0.025 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated at 85 C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=40-80%; 16 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (166 mg, 23% yield) as a pale yellow solid.
[0866] MS (ES.sup.+) C.sub.24H.sub.29ClN.sub.6O.sub.3S requires: 516, found: 517 [M+H].sup.+.
Step 2
[0867] ##STR00182##
(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0868] To a solution of the product from the previous step (32 mg, 0.021 mmol) in CH.sub.2Cl.sub.2 (215 L) was added TFA (33, 0.43 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=20-60%; 20 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (12.2 mg, 91% yield) as an off-white solid.
[0869] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 7.15 (d, J=1.0 Hz, 1H), 7.10 (s, 1H), 6.20 (s, 1H), 4.58 (s, 1H), 4.19 (s, 1H), 4.03 (dd, J=11.6, 3.9 Hz, 1H), 3.83 (d, J=11.7 Hz, 1H), 3.73 (dd, J=11.7, 3.2 Hz, 1H), 3.59 (td, J=12.0, 3.1 Hz, 1H), 3.53 (d, J=4.1 Hz, 6H), 3.42 (td, J=13.1, 3.8 Hz, 1H), 1.37 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.16H.sub.21ClN.sub.6O.sub.2S requires: 396/398, found 397/399 [M+H].sup.+.
EXAMPLE 14
[0870] ##STR00183##
(R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
Step 1
[0871] ##STR00184##
(R)-((2-(2-((4-methoxybenzyl)amino)-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0872] A solution of (R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.sup.6-sulfanone (synthesized as described for Example 13, step 1) (50 mg, 0.034 mmol), methylboronic acid (2.410 mg, 0.040 mmol) and K.sub.2CO.sub.3 (11.6 mg, 0.084 mmol) in dioxane (153 L) and water (15 L) was degassed with N.sub.2 for 30 seconds PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.4 mg, 1.7 mol) was added and the mixture was degassed with N.sub.2 for an additional 30 seconds. and the resulting mixture was heated at 120 C. for 6 h in a microwave reactor. The reaction mixture was cooled to RT, filtered through CELITE, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 26 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (13.5 mg, 56% yield) as a pale yellow solid.
[0873] MS (ES.sup.+) C.sub.25H.sub.32N.sub.6O.sub.3S requires: 496, found: 497 [M+H].sup.+.
Step 2
[0874] ##STR00185##
(R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0875] To a solution of the product from the previous step (13.5 mg, 0.019 mmol) in CH.sub.2Cl.sub.2 (186 L) was added TFA (29 L, 0.37 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (8.6 mg, 76% yield) as an off-white solid.
[0876] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 7.69 (s, 1H), 7.47 (s, 1H), 6.04 (s, 1H), 4.51-4.45 (m, 1H), 4.09 (d, J=12.9 Hz, 1H), 4.00 (dd, J=11.5, 3.9 Hz, 1H), 3.80 (d, J=11.5 Hz, 1H), 3.72 (dd, J=11.6, 3.2 Hz, 1H), 3.57 (td, J=11.9, 3.2 Hz, 1H), 3.49 (s, 6H), 3.32-3.24 (m, overlap MeOH, 1H), 2.55 (s, 3H), 1.29 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.24N.sub.6O.sub.2S requires: 376, found 377 [M+H].sup.+.
EXAMPLE 15
[0877] ##STR00186##
(R)-6-amino-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinonitrile
[0878] ##STR00187##
(R)-6-amino-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinonitrile
[0879] A microwave vial was charged with Example 13 (95 mg, 0.076 mmol), Pd.sub.2(dba).sub.3 (7.0 mg, 7.6 mol), DPPF (2.1 mg, 3.8 mol), zinc (0.75 mg, 0.011 mmol), dicyanozinc (8.9 mg, 0.076 mmol) and DMA (380 L). The vial was sealed and the reaction mixture was heated to 150 C. in a microwave reactor for 3 h. The reaction mixture was cooled to RT and directly purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 26 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (23.3 mg, 50% yield) as a pale yellow solid.
[0880] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 7.58 (s, 1H), 7.44 (s, 1H), 6.19 (s, 1H), 4.58 (s, 1H), 4.28-4.10 (m, 1H), 4.03 (dd, J=11.7, 3.9 Hz, 1H), 3.83 (d, J=11.7 Hz, 1H), 3.73 (dd, J=11.7, 3.2 Hz, 1H), 3.59 (td, J=12.0, 3.1 Hz, 1H), 3.54 (d, J=4.4 Hz, 6H), 3.41 (td, J=13.0, 4.0 Hz, 1H), 1.37 (d, J=6.9 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.21N.sub.7O.sub.2S requires: 387, found: 388 [M+H].sup.+.
EXAMPLE 16
[0881] ##STR00188##
Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
Step 1
[0882] ##STR00189##
Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0883] A reaction vial was charged with Int. T (300 mg, 0.60 mmol), Int. E (80 mg, 0.67 mmol), Cs.sub.2CO.sub.3 (655 mg, 2.01 mmol), RuPhos Pd G3 (56 mg, 0.067 mmol), RuPhos (31 mg, 0.067 mmol) and dioxane (4 mL). The reaction mixture was purged with N.sub.2, sealed and heated at 80 C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-50% acetone in hexanes) to afford the title compound (130 mg, 37% yield) as a white solid.
[0884] MS (ES.sup.+) C.sub.27H.sub.30N.sub.6O.sub.4S.sub.2 requires: 566, found: 567 [M+H].sup.+.
Step 2
[0885] ##STR00190##
Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0886] A reaction vial was charged with the product from the previous step (130 mg, 0.23 mmol), NaOH (184 mg, 4.6 mmol), H.sub.2O (1 mL) and MeOH (2 mL) and the mixture was heated at 70 C. for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was added MeOH (30 mL) and the resulting mixture was stirred for 5 min., filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=30-60%; 18 min; Column: Welch XB-C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (20 mg, 21% yield) as a white solid.
[0887] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.71 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90 (dd, J=5.0, 1.8 Hz, 1H), 7.53 (d, J=2.9 Hz, 1H), 7.40 (s, 1H), 5.95 (s, 1H), 4.47 (s, 1H), 4.05 (s, 1H), 3.96 (d, J=8.5 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.64 (d, J=11.4 Hz, 1H), 3.52 (t, J=13.9 Hz, 4H), 3.16 (s, 1H), 3.00 (s, 1H), 1.18 (dd, J=34.3, 27.3 Hz, 7H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+.
EXAMPLE 17a and 17b
[0888] ##STR00191##
(S)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone and
[0889] ##STR00192##
(R)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
Step 1
[0890] ##STR00193##
(S)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone and (R)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0891] To a solution of ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.sup.6-sulfanone (synthesis is similar to that described for Example 16) (350 mg, 0.63 mmol) in MeOH (6 mL) and THF (2 mL) was added NaOH (1.5 mL, 4 N aqueous) and the reaction mixture was heated to 60 C. and stirred for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-5% MeOH in CH.sub.2Cl.sub.2) to afford a mixture of the title compounds. The mixture of diastereomers was separated by Chiral SFC (Mobile phase: CO.sub.2/ethanol (1% MeOH Ammonia)=45/55; Flow rate: 80 g/min; 6.5 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK AD, 10 m, 20 mm250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 17a (43 mg, 18% yield, >99% ee) as a white solid and 17b (47 mg, 20% yield, >94% ee) as a white solid.
[0892] 17a ((R)-ethyl(methyl)-.sup.6-sulfanone or (S)-ethyl (methyl)-6-sulfanone): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.88 (d, J=5.0 Hz, 1H), 7.63-7.48 (m, 1H), 7.42 (d, J=2.0 Hz, 1H), 5.93 (s, 1H), 4.44 (s, 1H), 4.07 (d, J=12.7 Hz, 1H), 3.96 (dd, J=11.3, 3.2 Hz, 1H), 3.75 (d, J=11.3 Hz, 1H), 3.63 (dd, J=9.1, 5.7 Hz, 2H), 3.61 (d, J=7.5 Hz, 1H), 3.49 (td, J=11.8, 2.8 Hz, 1H), 3.38 (s, 3H), 3.15 (td, J=12.8, 3.6 Hz, 1H), 1.31 (t, J=7.4 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+; R.sub.t=2.72 min.
[0893] 17b ((R)-ethyl(methyl)-.sup.6-sulfanone or (S)-ethyl (methyl)-.sup.6-sulfanone): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.88 (d, J=5.0 Hz, 1H), 7.54 (d, J=3.4 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 5.93 (s, 1H), 4.47 (s, 1H), 4.05 (d, J=13.2 Hz, 1H), 3.96 (dd, J=11.1, 3.4 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.70-3.53 (m, 3H), 3.54-3.44 (m, 1H), 3.36 (d, J=13.0 Hz, 3H), 3.15 (td, J=12.7, 3.6 Hz, 1H), 1.32 (q, J=7.7 Hz, 3H), 1.21 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+; R.sub.t=3.28 min.
EXAMPLE 18 (18a and 18b)
[0894] ##STR00194##
(R)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone and
[0895] ##STR00195##
(S)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
Step 1
[0896] ##STR00196##
Cyclopropyl((2-(2-methoxy-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)-.SUP.6.-sulfanone
[0897] A suspension of Int. Q (590 mg, 1.79 mmol), Int. S (790 mg, 2.14 mmol) and K.sub.2CO.sub.3 (741 mg, 5.37 mmol) in dioxane (15 mL) and water (3 mL) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (73 mg, 0.090 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated to 130 C. in a microwave reactor for 4 h. The mixture was cooled to RT, the layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-2% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (910 mg, 95% yield) as a yellow solid.
[0898] MS (ES.sup.+) C.sub.27H.sub.34N.sub.6O.sub.4S requires: 538, found: 539 [M+H].sup.+.
Step 2
[0899] ##STR00197##
(S)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone and (R)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[0900] To a solution of the product from the previous step (910 mg, 1.69 mmol) in CH.sub.2Cl.sub.2 (7 mL) was added TFA (2.5 mL, 34 mmol) and the resulting mixture was stirred at 45 C. for 16 h. The mixture was cooled to RT and neutralized with 6 N NaOH to pH=7, followed by the addition of sat. aq. NaHCO.sub.3 (30 mL) and the mixture was stirred vigorously for 5 min. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-3% MeOH in CH.sub.2Cl.sub.2) to afford a mixture of the title compounds (650 mg, 92% yield). The mixture of diastereomers was separated by Chiral SFC (Mobile phase: CO.sub.2/MeOH (0.2% MeOH Ammonia)=45/55; Flow rate: 80 g/min; 7 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK AD, 10 m, 20 mm250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, compounds 18a (167 mg, 26% yield, 98.6% ee) as a white solid and 18b (230 mg, 35% yield, >99% ee) as a white solid; (R)-cyclopropyl(methyl)-.sup.6-sulfanone and (S)-cyclopropyl(methyl)-.sup.6-sulfanone
[0901] 18a: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 6.87 (s, 1H), 6.67 (s, 1H), 6.00 (s, 2H), 5.90 (s, 1H), 4.44-4.34 (m, 1H), 4.02 (d, J=13.2 Hz, 1H), 3.92 (dd, J=11.3, 3.2 Hz, 1H), 3.77 (s, 3H), 3.72 (d, J=11.4 Hz, 1H), 3.60 (dd, J=11.3, 3.1 Hz, 1H), 3.55 (s, 3H), 3.45 (td, J=11.6, 2.6 Hz, 1H), 3.09 (td, J=12.7, 3.8 Hz, 1H), 3.06-2.94 (m, 1H), 1.25-1.19 (m, 1H), 1.16 (app. d, overlap, J=6.6 Hz, 3H), 1.14-1.02 (m, 3H); MS (ES.sup.+) C.sub.19H.sub.26N.sub.6O.sub.3S requires: 418, found: 419 [M+H].sup.+; R.sub.t=3.03 min.
[0902] 18b: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.88 (d, J=1.2 Hz, 1H), 6.68 (d, J=1.1 Hz, 1H), 5.99 (s, 2H), 5.90 (s, 1H), 4.43-4.34 (m, 1H), 4.03 (d, J=13.3 Hz, 1H), 3.92 (dd, J=11.3, 3.6 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.3 Hz, 1H), 3.60 (dd, J=11.4, 3.1 Hz, 1H), 3.55 (s, 3H), 3.45 (td, J=11.8, 3.1 Hz, 1H), 3.09 (td, J=12.8, 3.8 Hz, 1H), 3.01 (tt, J=7.9, 4.9 Hz, 1H), 1.25-1.19 (m, 1H), 1.16 (app. d, overlap, J=6.7 Hz, 3H), 1.14-1.05 (m, 2H); MS (ES.sup.+) C.sub.19H.sub.26N.sub.6O.sub.3S requires: 418, found: 419 [M+H].sup.+; R.sub.t=3.71 min.
[0903] Alternatively, Example 18b can also be prepared from Int. CC, Isomer 1b.
EXAMPLE 19
[0904] ##STR00198##
(R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
Step 1
[0905] ##STR00199##
(R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0906] A suspension of Int. K (278 mg, 1.00 mmol), Int. D (304 mg, 1.00 mmol), Na.sub.2CO.sub.3 (212 mg, 2.00 mmol) and PdCl.sub.2(dppf) (75 mg, 0.1 mmol) in dioxane (20 mL) and H.sub.2O (4 mL) was degassed with Ar (3). The reaction mixture was heated to 80 C. and stirred for 16 h under an atmosphere of Ar. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by Prep-TLC (66% EtOAc in petroleum ether) to afford the title compound (130 mg, 31% yield) as a white solid.
[0907] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.98 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 5.95 (s, 1H), 4.42 (s, 1H), 4.01 (dd, J=43.8, 11.0 Hz, 2H), 3.75 (d, J=11.2 Hz, 1H), 3.63 (d, J=9.8 Hz, 1H), 3.46 (d, J=22.0 Hz, 7H), 3.16 (d, J=12.4 Hz, 1H), 1.20 (d, J=6.6 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.21ClN.sub.6O.sub.2S requires: 420, found: 421 [M+H].sup.+.
EXAMPLE 20
[0908] ##STR00200##
(R)-4-(4-((dimethyl(oxo)-.SUP.6.-sulfanylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile
Step 1
[0909] ##STR00201##
(R)-4-(4-((dimethyl(oxo)-.SUP.6.-sulfanylidene)amino)-6-(3-methylmorpholino)-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile
[0910] A mixture of Example 19 (40 mg, 0.096 mmol), ZnCN.sub.2 (113 mg, 0.96 mmol) and Pd(PPh.sub.3).sub.4 (110 mg, 0.096 mmol) in DMF (3 mL) was degassed with Ar. The reaction mixture was heated at 150 C. for 2 h in a microwave reactor. The mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B=MeCN; Gradient: B=35-65%; 18 min; 30 mL/min; column: Welch XB-C18 21.2250 mm, 10 m) to afford the title compound (13 mg, 33% yield) as a white solid.
[0911] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.38 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.61 (d, J=3.0 Hz, 1H), 5.96 (s, 1H), 4.44 (s, 1H), 4.09 (d, J=12.5 Hz, 1H), 3.97 (d, J=8.5 Hz, 1H), 3.75 (d, J=11.5 Hz, 1H), 3.64 (d, J=8.7 Hz, 1H), 3.53-3.41 (m, 7H), 3.16 (t, J=10.9 Hz, 1H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.21N.sub.7O.sub.2S requires: 411, found: 412 [M+H].sup.+.
EXAMPLE 21
[0912] ##STR00202##
(R)-dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
Step 1
[0913] ##STR00203##
(R)-dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methyl-morpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0914] A mixture of Example 19 (30 mg, 0.07 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (9 mg, 0.07 mmol), PdCl.sub.2(dppf) (5 mg, 0.007 mmol) and Cs.sub.2CO.sub.3 (70 mg, 0.21 mmol) in dioxane (6 mL) and H.sub.2O (1 mL) was degassed with Ar and heated to 80 C. and stirred for 16 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in water, B=MeCN; Gradient: B=30-60%; 18 min; 30 mL/min; column: Welch XB-C18 21.2250 mm, 10 m) to afford the title compound (4 mg, 14% yield) as a white solid.
[0915] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.50 (s, 1H), 7.75 (s, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.33 (s, 1H), 5.91 (s, 1H), 4.44 (s, 1H), 4.07 (d, J=13.4 Hz, 1H), 3.96 (d, J=7.7 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.64 (d, J=8.5 Hz, 1H), 3.50 (d, J=9.0 Hz, 1H), 3.44 (s, 6H), 2.59 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.
EXAMPLE 22
[0916] ##STR00204##
(R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino-.SUP.6.-sulfanone
Step 1
[0917] ##STR00205##
(R)-dimethyl((6-(3-methylmorpholino)-2-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0918] A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine (60 mg, 0.12 mmol), Int. D (37 mg, 0.12 mmol), Na.sub.2CO.sub.3 (25 mg, 0.24 mmol) and PdCl.sub.2(dppf) (9.0 mg, 0.012 mmol) in dioxane (6 mL) and H.sub.2O (1 mL) was degassed with Ar (3). The reaction mixture was heated to 80 C. and stirred for 16 h under an atmosphere of Ar. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by Prep-TLC (66% EtOAc in petroleum ether) to afford the title compound (45 mg, 60% yield) as a yellow oil.
[0919] MS (ES.sup.+) C.sub.36H.sub.35N.sub.7O.sub.2S requires: 629, found: 630 [M+H].sup.+.
Step 2
[0920] ##STR00206##
(R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0921] A solution of the product from the previous step in TFA (1 mL) and CH.sub.2Cl.sub.2 (4 mL) was stirred at RT for 4 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in water, B=MeCN; Gradient: B=25-65%; 18 min; 30 mL/min; column: Welch XB-C18 21.2250 mm, 10 um) to afford the title compound (14 mg, 52% yield) as a pale yellow solid.
[0922] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.72 (s, 1H), 8.93 (s, 1H), 8.64 (d, J=4.7 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H), 5.98 (s, 1H), 4.46 (s, 1H), 4.08 (d, J=12.9 Hz, 1H), 3.97 (d, J=8.0 Hz, 1H), 3.76 (d, J=11.4 Hz, 1H), 3.64 (d, J=8.4 Hz, 1H), 3.53-3.43 (m, 7H), 3.22-3.07 (m, 1H), 1.21 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.21N.sub.7O.sub.2S requires: 387, found: 388 [M+H].sup.+.
EXAMPLE 23
[0923] ##STR00207##
(R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0924] ##STR00208##
(R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-dimethyl-.SUP.6.-sulfanone
[0925] A mixture of Int. D (0.21 g, 0.69 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.27 g, 0.83 mmol), K.sub.3PO.sub.4 (0.44 g, 2.1 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (40 mg, 0.055 mmol) in dioxane (9 mL) and water (2 mL) was degassed with a stream of N.sub.2 for ten minutes and then heated to 85 C. for 4 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and H.sub.2O (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (230 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (8 mL) and THF (2 mL) at room temperature and to this solution was added concentrated HCl solution (ca. 12 N, 0.1 mL). The reaction mixture was heated to 60 C. for 20 minutes then stirred at RT for 18 h. To the reaction mixture was added sat. aq. NaHCO.sub.3 (3 mL) and the mixture was concentrated under reduced pressure. The residue was partitioned between CH.sub.2Cl.sub.2 (25 mL) and H.sub.2O (25 mL), the layers were separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (225 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced. The residue was purified via silica gel chromatography (10-30% CH.sub.3CN in CH.sub.2Cl.sub.2) to afford the title compound (0.26 g, quantitative yield) as a yellow solid.
[0926] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.08 (d, J=0.75 Hz, 1H), 8.20 (dd, J=7.28, 1.00 Hz, 1H), 7.61 (d, J=8.28 Hz, 1H), 7.46 (dd, J=8.28, 7.28 Hz, 1H), 5.91 (s, 1H), 4.39-4.51 (m, 1H), 3.97-4.19 (m, 2H), 3.74-3.90 (m, 2H), 3.56-3.73 (m, 2H), 3.45 (d, J=1.51 Hz, 6H), 3.26-3.39 (m, 1H), 1.36 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.22N.sub.6O.sub.2S requires: 386, found: 387 [M+H].sup.+.
EXAMPLE 24
[0927] ##STR00209##
(R)-dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0928] ##STR00210##
(R)-dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino-.SUP.6.-sulfanone
[0929] A microwave vial was charged with Int. L (100 mg, 0.42 mmol), Int. D (65 mg, 0.21 mmol), Na.sub.2CO.sub.3 (133 mg, 1.26 mmol), Pd(dppf)Cl.sub.2 (24 mg, 0.03 mmol), dioxane (3 mL) and H.sub.2O (1 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was heated at 80 C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=25-55%; 18 min; Column: Welch XB-C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (8 mg, 10% yield) as a white solid.
[0930] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.06 (d, J=5.2 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=5.3 Hz, 1H), 6.67 (s, 1H), 5.87 (s, 1H), 4.42-4.36 (m, 1H), 4.07-4.01 (m, 1H), 3.92 (d, J=12.1 Hz, 1H), 3.72 (d, J=11.3 Hz, 1H), 3.61 (d, J=8.5 Hz, 1H), 3.45 (d, J=2.5 Hz, 6H), 3.31 (s, 1H), 3.09 (s, 1H), 2.80 (d, J=4.8 Hz, 3H), 1.16 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.24N.sub.6O.sub.2S requires: 376, found: 377 [M+H].sup.+.
EXAMPLE 25
[0931] ##STR00211##
(R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0932] ##STR00212##
(R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0933] A microwave vial was charged with Int. V (34 mg, 0.06 mmol), 4-bromo-6-methoxy-1H-pyrrolo[2,3-b]pyridine (14 mg, 0.06 mmol), CuI (1.2 mg, 0.006 mmol), LiCl (5 mg, 0.12 mmol), Pd(PPh.sub.3).sub.4 (7 mg, 0.006 mmol) and DMF (5 mL). The vial was purged with Ar, sealed and heated at 120 C. for 2 h in a microwave reactor. The reaction mixture was cooled to RT, sat. aq. KF (10 mL) was added and the aqueous layer was extracted with EtOAc (310 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=40-70%; 18 min; Column: Welch XB-C18, 10 m, 21.2250 mm) to afford the title compound (5 mg, 20% yield) as a white solid.
[0934] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.55 (s, 1H), 7.35 (s, 1H), 7.26 (d, J=11.3 Hz, 2H), 5.92 (s, 1H), 4.43 (s, 1H), 4.03 (d, J=12.7 Hz, 1H), 3.95 (d, J=7.6 Hz, 1H), 3.91 (s, 3H), 3.75 (d, J=11.2 Hz, 1H), 3.63 (d, J=8.8 Hz, 1H), 3.46 (d, J=21.0 Hz, 7H), 3.14 (t, J=11.0 Hz, 1H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.3S requires: 416, found: 417 [M+H].sup.+.
EXAMPLE 26
[0935] ##STR00213##
(R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0936] ##STR00214##
(R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0937] A microwave vial was charged with Int. V (150 mg, 0.268 mmol), Int. M (170 mg, 0.35 mmol), LiCl (23 mg, 0.54 mmol), CuI (5 mg, 0.027 mmol), Pd(PPh.sub.3).sub.4 (31 mg, 0.027 mmol) and DMF (2 mL). The reaction vial was degassed by bubbling Ar into it the solution, sealed and heated to 120 C. for 90 min. in a microwave reactor. The reaction was resubmitted to the microwave cycle until it was judged completed by LCMS with new palladium catalyst added and the reaction vial degassed with Ar prior to each cycle. The reaction mixture was diluted with EtOAc (20 mL), filtered through CELITE, and concentrated under reduced pressure. The residue was taken up in a 1 N HCl (10 mL) and washed with Et.sub.2O (5 mL) and hexanes (5 mL). The aqueous layer was then adjusted to pH >12 with 2 M aq. NaOH and extracted with CH.sub.2Cl.sub.2 (35 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Mobile phase: A=0.1% HCO.sub.2H/H.sub.2O, B=0.1% HCO.sub.2H/MeCN; Gradient: B=0-30%; 15 min; Column: Biotage SNAP Ultra C18 30 g, HP-Sphere C18 25 m). The combined fractions were treated with 0.1 M aq. HCl, concentrated under reduced pressure and lyophilized to afford the titled compound (33.2 mg, 32% yield) as a white solid.
[0938] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.71 (d, J=5.27 Hz, 1H) 8.52 (s, 1H) 8.16 (d, J=5.02 Hz, 1H) 5.91 (s, 1H) 4.36-4.52 (m, 1H) 4.13-4.25 (m, 1H) 4.08 (br dd, J=11.54, 3.76 Hz, 1H) 3.82-3.91 (m, 1H) 3.79 (br d, J=2.76 Hz, 1H) 3.64 (br d, J=3.01 Hz, 1H) 3.46-3.52 (m, 1H) 3.43 (s, 6H) 3.29-3.39 (m, 1H) 1.37 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.21N.sub.7O.sub.2S requires: 387, found: 388 [M+H].sup.+.
EXAMPLE 27
[0939] ##STR00215##
(R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
Step 1
[0940] ##STR00216##
(R)-((2-(2-cyclopropyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0941] A mixture of Int. U (50 mg, 0.13 mmol), Int. V (72 mg, 0.13 mmol), CuI (2 mg, 0.013 mmol), LiCl (3 mg, 0.26 mmol), Pd(PPh.sub.3).sub.4 (15 mg, 0.013 mmol) and DMF (5 mL) was degassed with Ar (3) and then heated at 120 C. for 2 h in a microwave reactor. The mixture was cooled to RT, sat. aq. Na.sub.2S.sub.2O.sub.3 (10 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% EtOAc in hexanes) to afford the title compound (30 mg, 40% yield) as a yellow solid.
[0942] MS (ES.sup.+) C.sub.28H.sub.32N.sub.6O.sub.4S.sub.2 requires: 580, found: 581 [M+H].sup.+.
Step 2
[0943] ##STR00217##
(R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0944] A mixture of the product from the previous step (30 mg, 0.05 mmol), NaOH (4 mg, 0.1 mmol), H.sub.2O (1 mL) and MeOH (3 mL) was heated at 60 C. and stirred for 2 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=45-75; 15 min; Column: Welch XB-C18, 10 m, 21.2250 mm) to afford the title compound (2 mg, 10% yield) as a white solid.
[0945] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.58 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.80 (d, J=5.0 Hz, 1H), 7.11 (s, 1H), 5.88 (s, 1H), 4.44 (s, 1H), 4.04 (d, J=12.9 Hz, 1H), 3.95 (d, J=10.9 Hz, 1H), 3.74 (d, J=11.4 Hz, 1H), 3.63 (d, J=8.2 Hz, 1H), 3.46 (d, J=25.8 Hz, 7H), 2.03 (s, 1H), 1.20 (d, J=6.7 Hz, 3H), 1.06-0.97 (m, 2H), 0.86 (d, J=3.0 Hz, 2H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+.
EXAMPLE 28
[0946] ##STR00218##
(R)-dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
Step 1
[0947] ##STR00219##
(R)-((2-(2,3-diaminopyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0948] A microwave vial was charged with Int. J (450 mg crude, assumed 1.07 mmol), Int. D (250 mg, 0.82 mmol), Na.sub.2CO.sub.3 (260 mg, 2.46 mmol), Pd(dppf)Cl.sub.2 (48 mg, 0.06 mmol), dioxane (12 mL) and H.sub.2O (4 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was heated at 80 C. and stirred for 3 h. The reaction mixture was cooled to RT, filtered through CELITE, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-15% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (350 mg, 100% yield) as a brown solid.
[0949] MS (ES.sup.+) C.sub.16H.sub.23N.sub.7O.sub.2S requires: 377, found: 378 [M+H].sup.+.
Step 2
[0950] ##STR00220##
(R)-dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methyl-morpholino)pyrimidin-4-yl)imino-sulfanone
[0951] A mixture of the product from the previous step (150 mg, 0.4 mmol), HOAc (0.2 mL) and PPA (1 g) were charged in a 20 mL microwave vial and purged with N.sub.2 for 1 min. The vial was sealed and heated at 150 C. for 1.5 h. The reaction mixture was cooled to RT, sat. aq. K.sub.2CO.sub.3 (30 mL) was added and the aqueous layer was extracted with EtOAc (350 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, BMeCN; Gradient: B=25-55%; 18 min; Column: Welch XB-C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (20 mg, 12% yield) as a white solid.
[0952] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.99 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 7.89 (d, J=5.1 Hz, 1H), 5.97 (s, 1H), 4.47 (s, 1H), 4.14 (s, 1H), 3.95 (d, J=11.1 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H), 3.63 (d, J=8.3 Hz, 1H), 3.47 (s, 7H), 3.19-3.11 (m, 1H), 2.58 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.23N.sub.7O.sub.2S requires: 401, found: 402 [M+H].sup.+.
EXAMPLE 29
[0953] ##STR00221##
(R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0954] ##STR00222##
(R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0955] A reaction vial was charged with Int. D (120 mg, 0.39 mmol), 2-cyclopropyl-1H-benzo[d]imidazole (94 mg, 0.59 mmol), Pd.sub.2dba.sub.3 (18 mg, 0.02 mmol), XPhos (16 mg, 0.04 mmol), Cs.sub.2CO.sub.3 (380 mg, 1.17 mmol) and dioxane (6 mL). The vial was purged with N.sub.2 for 2 min., sealed and heated to 150 C. for 1 h in a microwave reactor. The reaction mixture was cooled to RT, filtered through CELITE, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=40-70%; 15 min; Column: Agela C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (83.0 mg, 50% yield) as a white solid.
[0956] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.10 (dd, J=6.8, 2.3 Hz, 1H), 7.53 (dd, J=6.5, 2.2 Hz, 1H), 7.24-7.14 (m, 2H), 5.93 (s, 1H), 4.36 (s, 1H), 3.94 (dd, J=16.4, 8.5 Hz, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.61 (dd, J=11.4, 2.9 Hz, 1H), 3.50-3.44 (m, 1H), 3.42 (s, 6H), 3.17 (td, J=13.0, 3.9 Hz, 1H), 3.09-3.01 (m, 1H), 1.21 (d, J=6.7 Hz, 3H), 1.17-1.11 (m, 2H), 1.09-1.02 (m, 2H); MS (ES.sup.+) C.sub.18H.sub.22N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+.
EXAMPLE 30
[0957] ##STR00223##
(R)-dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0958] ##STR00224##
(R)-dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0959] A microwave vial was charged with Int. D (50 mg, 0.165 mmol), 2-methylbenzimidazole (44 mg, 0.329 mmol), XPhos Pd G2 (6.5 mg, 0.008 mmol) and K.sub.3PO.sub.4 (70 mg, 0.329 mmol). The vial was sealed, purged with Ar, dioxane (2 mL) was added and the solution was degassed by bubbling Ar and the resulting mixture was heated in at 150 C. for 1 h in a microwave reactor. The reaction mixture was cooled to RT, filtered through CELITE, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by flash chromatography (1-5% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (62 mg, 94% yield) as a white solid.
[0960] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.22-8.39 (m, 1H) 7.63-7.89 (m, 1H) 7.30-7.54 (m, 2H) 5.86 (s, 1H) 4.25-4.41 (m, 1H) 4.05 (dd, J=11.54, 3.76 Hz, 1H) 3.90-3.98 (m, 1H) 3.70-3.89 (m, 2H) 3.53-3.68 (m, 1H) 3.26-3.51 (m, 7H) 3.06 (s, 3H) 1.36 (d, J=6.78 Hz, 3H) 1.10-1.32 (m, 1H) 0.91 (s, 1H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.
EXAMPLE 31
[0961] ##STR00225##
Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0962] Synthesis is similar to that described for Example 11, using Int. I.
[0963] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.79 (s, 1H), 7.67 (t, J=2.7 Hz, 1H), 7.45 (s, 1H), 5.90 (s, 1H), 4.46 (s, 1H), 4.04 (s, 1H), 3.96 (d, J=7.8 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.64 (d, J=10.5 Hz, 1H), 3.51 (dd, J=32.0, 6.9 Hz, 4H), 3.14 (s, 1H), 3.01 (d, J=7.6 Hz, 1H), 1.21 (t, J=7.1 Hz, 5H), 1.09 (d, J=7.8 Hz, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+.
EXAMPLE 32
[0964] ##STR00226##
(S)-((6-(3-(fluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0965] Synthesis is similar to that described for Example 11, using Int. O and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.
[0966] .sup.1H NMR (400 MHz, CDCl.sub.3) 10.35 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.01 (d, J=5.1 Hz, 1H), 7.61-7.41 (m, 2H), 5.94 (s, 1H), 5.26-5.02 (m, 1H), 4.53 (s, 1H), 4.31-3.96 (m, 3H), 3.83-3.61 (m, 4H), 3.44 (d, J=4.8 Hz, 6H); MS (ES.sup.+) C.sub.18H.sub.21FN.sub.6O.sub.2S requires: 404, found: 405 [M+H].sup.+.
EXAMPLE 33
[0967] ##STR00227##
(S)-((6-(3-(difluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0968] Synthesis is similar to that described for Example 11, using Int. W and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.
[0969] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.28 (d, J=5.1 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 7.51 (dd, J=21.8, 3.5 Hz, 2H), 6.34 (td, J=56.1, 5.7 Hz, 1H), 6.06 (s, 1H), 4.25 (d, J=12.3 Hz, 1H), 4.06 (dd, J=11.4, 3.6 Hz, 2H), 3.78 (dd, J=12.3, 3.2 Hz, 1H), 3.67 (td, J=11.8, 3.1 Hz, 1H), 3.49 (t, J=7.2 Hz, 7H), 3.43 (dd, J=12.7, 3.8 Hz, 1H), 3.34 (s, 2H), 3.32 (s, 2H); MS (ES.sup.+) C.sub.18H.sub.20F.sub.2N.sub.6O.sub.2S requires: 422, found: 423 [M+H].sup.+.
EXAMPLE 34
[0970] ##STR00228##
(R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
Step 1
[0971] ##STR00229##
(R)-((2-((3-fluoro-2-nitrophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0972] A reaction vial was charged with Int. D (250 mg, 0.82 mmol), 3-fluoro-2-nitroaniline (192 mg, 1.23 mmol), Pd.sub.2dba.sub.3 (38 mg, 0.041 mmol), XPhos (35 mg, 0.082 mmol), Cs.sub.2CO.sub.3 (800 mg, 2.47 mmol) and dioxane (10 mL). The vial was purged with N.sub.2 for 2 min. and the reaction mixture was heated at 100 C. and stirred for 16 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (50-75% EtOAc in hexanes) to afford the title compound (290 mg, 74% yield) as an orange solid.
[0973] MS (ES.sup.+) C.sub.17H.sub.21FN.sub.6O.sub.4S requires: 424, found: 425 [M+H].sup.+.
Step 2
[0974] ##STR00230##
(R)-((2-((2-amino-3-fluorophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0975] A reaction vessel was charged with the product from the previous step (280 mg, 0.66 mmol), 10% Pd/C (50 mg, 0.047 mmol) and EtOH (40 mL) under an atmosphere of N.sub.2. The suspension was degassed with N.sub.2 for 1 minute and purged with H.sub.2 for 1 minute. The reaction mixture was stirred under an atmosphere of H.sub.2 at 1 atm for 2 h. The reaction mixture was purged with N.sub.2, filtered through CELITE and concentrated under reduced pressure to afford the title compound (260 mg, quantitative yield) as a red solid.
[0976] MS (ES.sup.+) C.sub.17H.sub.23FN.sub.6O.sub.2S requires: 394, found: 395 [M+H].sup.+.
Step 3
[0977] ##STR00231##
(R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[0978] A mixture of the product from the previous step (260 mg, 0.66 mmol) and acetic acid (132 mg, 2.21 mmol) in PPA (5 g) was heated at 150 C. for 3 h. The reaction was cooled to RT, diluted with water (50 mL) and 5 N aq. NaOH was added to adjust to pH=14. The aqueous layer was extracted with EtOAc (350 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3 in water, B=MeCN; Gradient: B=35-65%; 15 min; Column: Agela C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (146 mg, 53% yield) as a yellow solid.
[0979] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.10 (d, J=8.2 Hz, 1H), 7.19 (td, J=8.2, 5.1 Hz, 1H), 7.06 (dd, J=10.6, 8.1 Hz, 1H), 5.92 (s, 1H), 4.35 (s, 1H), 4.03-3.85 (m, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.61 (dd, J=11.4, 2.9 Hz, 1H), 3.47 (td, J=11.9, 3.0 Hz, 1H), 3.40 (d, J=2.1 Hz, 6H), 3.17 (td, J=12.9, 3.8 Hz, 1H), 2.85 (s, 3H), 1.21 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.23FN.sub.6O.sub.2S requires: 418, found: 419 [M+H].sup.+.
EXAMPLE 35
[0980] ##STR00232##
(R)-1-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-benzo[d]imidazole-6-carbonitrile
Step 1
[0981] ##STR00233##
(R)-4-amino-3-((4-((dimethyl(oxo-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)amino)benzonitrile
[0982] To a solution of (R)-3-((4-((dimethyl(oxo)-.sup.6-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)amino)-4-nitrobenzonitrile (synthesis is similar to that described for Example 34, step 1) (110 mg, 0.255 mmol) in EtOH (1.3 mL) were added ammonium chloride (54.5 mg, 1.02 mmol), water (425 L), and iron (56.9 mg, 1.02 mmol) and the resulting mixture was stirred at 100 C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (5-20% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (83 mg, 81% yield) as a yellow solid.
[0983] MS (ES.sup.+) C.sub.18H.sub.23N.sub.7O.sub.2S requires: 401, found: 402 [M+H].sup.+.
Step 2
[0984] ##STR00234##
(R)-1-(4-((dimethyl(oxo-sulfaneylidene)amino)-6-(3-methylmorpholino)-pyrimidin-2-yl)-1H-benzo[d]imidazole-6-carbonitrile
[0985] To a solution of the product from the previous step (30 mg, 0.037 mmol) in toluene (75 L) were added triethyl orthoformate (12 L, 0.075 mmol) and Ts-OH hydrate (0.71 mg, 3.7 mol) and the resulting mixture was heated at 110 C. and stirred for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 16 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (7.9 mg, 33% yield) as a white solid.
[0986] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 9.36 (s, 1H), 9.25-9.22 (m, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.69 (dd, J=8.4, 1.6 Hz, 1H), 5.91 (s, 1H), 4.47-4.39 (m, 1H), 4.08-3.98 (m, 2H), 3.82 (d, J=11.5 Hz, 1H), 3.75 (dd, J=11.5, 3.2 Hz, 1H), 3.60 (td, J=12.0, 3.2 Hz, 1H), 3.46 (s, 6H), 3.33-3.27 (m, overlap MeOH, 1H), 1.33 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.21N.sub.7O.sub.2S requires: 411, found: 412 [M+H].sup.+.
EXAMPLE 36
[0987] ##STR00235##
(R)-dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0988] ##STR00236##
(R)-dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[0989] To a suspension of (R)-((2-((2-aminopyridin-3-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.sup.6-sulfanone (synthesis is similar to that described for Example 34, step 2) (38 mg, 0.10 mmol) in triethyl orthoacetate (4 mL) was added p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) and the resulting mixture was heated to 50 C. for 16 h. The reaction mixture was cooled to RT and directly purified by flash chromatography (0-10% MeOH in CH.sub.2Cl.sub.2 with 0.5% of aq. NH.sub.4OH) to afford the title compound (20 mg, 0.05 mmol) as a solid.
[0990] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.63-8.83 (m, 1H) 8.52 (dd, J=4.77, 1.25 Hz, 1H) 7.20-7.34 (m, 2H) 5.82 (s, 1H) 4.17-4.39 (m, 1H) 4.04 (dd, J=11.54, 3.51 Hz, 1H) 3.91 (br d, J=12.30 Hz, 1H) 3.82 (d, J=11.54 Hz, 1H) 3.73 (dd, J=11.54, 3.01 Hz, 1H) 3.59 (td, J=11.86, 3.14 Hz, 1H) 3.27-3.45 (m, 7H) 3.04 (s, 3H) 1.34 (d, J=7.03 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.23N.sub.7O.sub.2S requires: 401, found: 402 [M+H].sup.+.
EXAMPLE 37
[0991] ##STR00237##
((2-(2-Aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
Step 1
[0992] ##STR00238##
((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
[0993] To a solution of (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described, Int. B, step 1) (4.6 g, 18.5 mmol) and Int. F (2.5 g, 18.5 mmol) in dioxane (80 mL) was added Pd.sub.2(dba).sub.3 (850 mg, 0.925 mmol), XantPhos (2.14 g, 3.7 mmol) and K.sub.2CO.sub.3 (6.4 g, 46 mmol) under an atmosphere of N.sub.2 and the resulting mixture was heated at 90 C. and stirred for 4 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (25-70% EtOAc in hexanes) to afford the title compound (1.8 g, 28% yield) as a white solid.
[0994] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 5.86 (s, 1H), 5.07-4.74 (m, 5H), 4.23 (s, 1H), 3.87 (dd, J=11.3, 3.5 Hz, 2H), 3.65 (d, J=11.5 Hz, 1H), 3.53 (dd, J=11.5, 2.9 Hz, 1H), 3.43-3.31 (m, 4H), 3.05 (d, J=3.6 Hz, 1H), 1.12 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.13H.sub.19ClN.sub.4O.sub.3S requires: 346, found: 347 [M+H].sup.+.
Step 2
[0995] ##STR00239##
((2-(2-Aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
[0996] To a solution of the product from the previous step (120 mg, 0.34 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (61 mg, 0.51 mmol) in dioxane (4 mL) and H.sub.2O (1 mL) were added Pd(dppf)C12 (25 mg, 0.034 mmol) and K.sub.2CO.sub.3 (141 mg, 1.02 mmol) under an atmosphere of N.sub.2 and the resulting mixture was heated at 90 C. and stirred for 16 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=20-50%; 18 min; Column: Agela C18, 10 m, 150 , 21.2 mm250 mm) to afford the title compound (42 mg, 31% yield) as a white solid.
[0997] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.99 (d, J=5.2 Hz, 1H), 7.50-7.03 (m, 2H), 5.97 (d, J=58.0 Hz, 3H), 5.10-4.75 (m, 5H), 4.49-4.26 (m, 1H), 4.15-3.97 (m, 1H), 3.95-3.88 (m, 1H), 3.71 (d, J=11.3 Hz, 1H), 3.60 (dd, J=11.4, 2.8 Hz, 1H), 3.52 (d, J=2.0 Hz, 3H), 3.45 (s, 1H), 3.10 (d, J=3.5 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.3S requires: 404, found: 405 [M+H].sup.+.
EXAMPLES 38a and 38b
[0998] ##STR00240##
(R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone and
[0999] ##STR00241##
(S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
[1000] Synthesis is similar to that described for Example 29, using the intermediate from the first step of the Example 37 procedure. The mixture of diastereomers (56 mg, 0.13 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2/MeOH (0.2% MeOH Ammonia)=55/45; Flow rate: 80 g/min; 6.3 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK OJ, 10 m, 20 mm250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 38a (14 mg, 25% yield, >99% ee) as a white solid and 38b (15 mg, 27% yield, >99% ee) as a white solid.
[1001] 38a ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.09-8.93 (m, 1H), 8.68-8.50 (m, 1H), 7.81-7.66 (m, 1H), 7.44-7.25 (m, 2H), 5.96-5.86 (m, 1H), 5.06 (dd, J=7.0, 1.1 Hz, 1H), 5.00-4.84 (m, 4H), 4.53-4.36 (m, 1H), 4.12-4.00 (m, 1H), 3.99-3.90 (m, 1H), 3.76-3.70 (m, 1H), 3.68-3.58 (m, 1H), 3.50 (dd, J=19.4, 1.5 Hz, 4H), 3.18 (d, J=3.6 Hz, 1H), 1.24-1.18 (m, 3H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.3S requires: 428, found: 429 [M+H].sup.+; R.sub.t=0.95 min.
[1002] 38b ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.02 (s, 1H), 8.60 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.49-7.20 (m, 2H), 5.92 (s, 1H), 5.11-5.01 (m, 1H), 4.99-4.85 (m, 4H), 4.47-4.39 (m, 1H), 4.15-4.02 (m, 1H), 3.99-3.91 (m, 1H), 3.72 (s, 1H), 3.66-3.59 (m, 1H), 3.51 (s, 4H), 3.23-3.11 (m, 1H), 1.22 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.3S requires: 428, found: 429 [M+H].sup.+; R.sub.t=1.31 min.
EXAMPLES 39a and 39b
[1003] ##STR00242##
(R)-((2-(2-aminopyridin-4-yl)-6-(((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone and
[1004] ##STR00243##
(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[1005] Synthesis is similar to that described for Example 24. The mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobile phase: n-hexane (0.1% DEA):EtOH (0.1% DEA)=70:30; Flow rate: 80 g/min; 20 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Gilson-281, AY 20250 mm, 10 m) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 39a (6.6 mg, 25% yield, >99% ee) as a white solid and 39b (7.1 mg, 27% yield, >99% ee) as a white solid.
[1006] 39a ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) 8.03-7.91 (m, 1H), 7.53 (s, 1H), 7.49 (dd, J=5.5, 1.4 Hz, 1H), 5.97 (s, 1H), 4.48 (d, J=4.6 Hz, 1H), 4.11 (d, J=12.0 Hz, 1H), 4.02 (dd, J=11.3, 3.6 Hz, 1H), 3.82 (d, J=11.4 Hz, 1H), 3.75 (dd, J=11.5, 3.0 Hz, 1H), 3.65-3.56 (m, 4H), 3.25 (td, J=12.8, 3.8 Hz, 1H), 3.01 (td, J=7.9, 4.0 Hz, 1H), 1.42 (dd, J=10.2, 5.4 Hz, 1H), 1.31 (dd, J=11.1, 6.2 Hz, 4H), 1.20 (dt, J=11.3, 5.7 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.2S requires: 388, found: 389 [M+H].sup.+; R.sub.t=11.35 min.
[1007] 39b ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) 7.97 (d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (dd, J=5.5, 1.3 Hz, 1H), 5.97 (s, 1H), 4.50 (s, 1H), 4.08 (d, J=12.7 Hz, 1H), 4.02 (dd, J=11.4, 3.7 Hz, 1H), 3.82 (d, J=11.3 Hz, 1H), 3.75 (dd, J=11.4, 3.0 Hz, 1H), 3.66-3.55 (m, 4H), 3.25 (td, J=12.9, 3.9 Hz, 1H), 3.05-2.97 (m, 1H), 1.41 (dd, J=10.6, 5.2 Hz, 1H), 1.31 (dd, J=11.8, 5.8 Hz, 4H), 1.20 (dt, J=11.1, 5.6 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.2S requires: 388, found: 389 [M+H].sup.+; R.sub.t=15.22 min.
[1008] Alternatively, Example 39a can also be prepared from Int. CC, Isomer 1b.
EXAMPLES 40a and 40b
[1009] ##STR00244##
(R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone and
[1010] ##STR00245##
(S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[1011] Synthesis is similar to that described for Example 29. The mixture of diastereomers (31 mg, 0.075 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2/MeOH (0.2% MeOH Ammonia)=50/50; Flow rate: 80 g/min; 10 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK OD, 10 m, 20 mm250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 40a (6.0 mg, 19% yield, >99% ee) as a white solid and 40b (5.0 mg, 16% yield, >98% ee) as a white solid.
[1012] 40a ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.01 (s, 1H), 8.60 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.33 (dd, J=13.5, 7.5 Hz, 2H), 5.90 (s, 1H), 4.53-4.29 (m, 1H), 3.95 (d, J=7.7 Hz, 2H), 3.74 (d, J=11.2 Hz, 1H), 3.63 (d, J=11.3 Hz, 1H), 3.50 (d, J=19.7 Hz, 4H), 3.17 (s, 1H), 3.04 (s, 1H), 1.22 (d, J=6.7 Hz, 5H), 1.13 (d, J=19.3 Hz, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; R.sub.t=3.50 min.
[1013] 40b ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.01 (s, 1H), 8.60 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.33 (ddd, J=15.1, 13.9, 6.7 Hz, 2H), 5.90 (s, 1H), 4.42 (s, 1H), 4.04 (s, 1H), 3.95 (dd, J=11.3, 3.4 Hz, 1H), 3.74 (d, J=11.4 Hz, 1H), 3.63 (dd, J=11.5, 2.9 Hz, 1H), 3.55-3.45 (m, 4H), 3.22-3.14 (m, 1H), 3.10-3.01 (m, 1H), 1.28-1.18 (m, 5H), 1.17-1.07 (m, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; R.sub.t=4.44 min.
[1014] Alternatively, Example 40b can also be prepared from Int. CC, Isomer 1b.
EXAMPLES 41a and 41b
[1015] ##STR00246##
(R)-methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetan-3-yl)-.SUP.6.-sulfanone and
[1016] ##STR00247##
(S)-methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetan-3-yl)-.SUP.6.-sulfanone
[1017] Synthesis is similar to that described for Example 29. The mixture of diastereomers (45 mg, 0.1 mmol) was separated by Chiral SFC (Mobile phase: n-Hexane (0.1% DEA): IPA (0.1% DEA)=35:65; Flow rate: 80 g/min; 20 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Gilson-281, sc 20250 mm, 10 m) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 41a (7.0 mg, 16% yield, 99% ee) as a white solid and 41b (4.0 mg, 9.0% yield, >93% ee) as a white solid.
[1018] 41a ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.24 (dd, J=6.1, 3.1 Hz, 1H), 7.58 (dd, J=6.0, 3.0 Hz, 1H), 7.29-7.15 (m, 2H), 6.02-5.86 (m, 1H), 4.89 (dddd, J=17.8, 15.5, 7.8, 6.8 Hz, 5H), 4.40 (s, 1H), 3.92 (d, J=11.3 Hz, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.65-3.55 (m, 1H), 3.44 (dd, J=15.6, 5.9 Hz, 4H), 3.22-3.12 (m, 1H), 2.88-2.77 (m, 3H), 1.29-1.12 (m, 3H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.3S requires: 442, found: 443 [M+H].sup.+; R.sub.t=13.15 min.
[1019] 41b ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.30-8.15 (m, 1H), 7.66-7.51 (m, 1H), 7.23 (dd, J=6.0, 3.2 Hz, 2H), 5.95 (s, 1H), 4.84 (s, 5H), 4.41-4.30 (m, 1H), 4.03-3.88 (m, 2H), 3.75-3.67 (m, 1H), 3.64-3.58 (m, 1H), 3.42 (s, 4H), 3.23-3.12 (m, 1H), 2.83 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.3S requires: 442, found: 443[M+H].sup.+; R.sub.t=17.06 min.
EXAMPLES 42a and 42b
[1020] ##STR00248##
(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone and
[1021] ##STR00249##
(S)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-.SUP.6.-sulfanone
[1022] Synthesis is similar to that described for Example 24. The mixture of diastereomers (100 mg, 0.18 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2/ethanol (1% MeOH Ammonia)=40/60; Flow rate: 80 g/min; 12 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK OJ, 10 m, 20 mm250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 42a (13 mg, 20% yield, >99% ee) as a white solid and 42b (20 mg, 31% yield, 96.7% ee) as a yellow solid.
[1023] 42a ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (400 MHz, MeOD-d.sub.4) 7.41 (s, 2H), 5.97 (s, 1H), 4.45 (s, 1H), 4.05 (dd, J=29.3, 11.7 Hz, 2H), 3.82 (d, J=11.6 Hz, 1H), 3.74 (d, J=8.8 Hz, 1H), 3.63-3.55 (m, 4H), 3.26-3.21 (m, 1H), 3.02-2.95 (m, 1H), 1.41 (s, 1H), 1.31 (dd, J=11.6, 5.8 Hz, 4H), 1.20 (d, J=7.5 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.23ClN.sub.6O.sub.2S requires: 422, found: 423 [M+H].sup.+; R.sub.t=4.27 min.
[1024] 42b ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (400 MHz, MeOD-d.sub.4) 7.25 (d, J=1.7 Hz, 2H), 5.88 (s, 1H), 4.36 (d, J=4.8 Hz, 1H), 4.00-3.86 (m, 2H), 3.70 (d, J=11.5 Hz, 1H), 3.62 (dd, J=11.5, 2.8 Hz, 1H), 3.52-3.43 (m, 4H), 3.18-3.10 (m, 1H), 2.92-2.83 (m, 1H), 1.31 (dd, J=11.3, 5.6 Hz, 1H), 1.22-1.17 (m, 4H), 1.09 (dd, J=9.5, 5.3 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.23ClN.sub.6O.sub.2S requires: 422, found: 423 [M+H].sup.+; R.sub.t=5.48 min.
[1025] Alternatively, Example 42a can also be prepared from Int. CC, Isomer 1b.
EXAMPLES 43a and 43b
[1026] ##STR00250##
(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone and
[1027] ##STR00251##
(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
[1028] Synthesis is similar to that described for Example 24. The mixture of diastereomers (36 mg, 0.089 mmol) was separated by Chiral SFC (Mobile phase: n-Hexane (0.1% DEA): EtOH (0.1% DEA)=60:40; Flow rate: 80 g/min; 17 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Gilson-281, AY 20*250 mm, 10 m) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 43a (9.0 mg, 23% yield, >99% ee) as a white solid and 43b (7.0 mg, 19% yield, >98% ee) as a white solid.
[1029] 43a ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) 7.98 (d, J=5.7 Hz, 1H), 7.59-7.37 (m, 2H), 5.99 (s, 1H), 5.12 (d, J=2.4 Hz, 1H), 5.07-4.96 (m, 4H), 4.52-4.41 (m, 1H), 4.16-4.06 (m, 1H), 4.00 (d, J=3.7 Hz, 1H), 3.82 (d, J=11.4 Hz, 1H), 3.75 (d, J=3.0 Hz, 1H), 3.60 (d, J=2.9 Hz, 1H), 3.52 (s, 3H), 3.25 (d, J=4.1 Hz, 1H), 1.29 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.3S requires: 404, found: 405 [M+H].sup.+; R.sub.t=9.34 min.
[1030] 43b ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) 7.86 (d, J=5.6 Hz, 1H), 7.44-7.29 (m, 2H), 5.87 (s, 1H), 4.99 (d, J=2.5 Hz, 1H), 4.89 (ddd, J=10.3, 7.5, 4.5 Hz, 4H), 4.40-4.32 (m, 1H), 4.02-3.85 (m, 2H), 3.64 (dt, J=11.4, 7.2 Hz, 2H), 3.47 (d, J=2.9 Hz, 1H), 3.39 (s, 3H), 3.16-3.07 (m, 1H), 1.17 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.3S requires: 404, found: 405 [M+H].sup.+; R.sub.t=12.75 min.
EXAMPLES 44a and 44b
[1031] ##STR00252##
(R)-cyclopropyhmethyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone and
[1032] ##STR00253##
(S)-cyclopropyl(methyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[1033] Synthesis is similar to that described for Example 30. The mixture of diastereomers (33.8 mg, 0.08 mmol) was separated by Chiral SFC (Mobile phase: n-Hexane (0.1% DEA): EtOH (0.1% DEA)=75:25; Flow rate: 80 g/min; 17 min; Column temperature: 35 C.; Back pressure: 100 bar; Column: Gilson-281, sc 20250 mm, 10 m) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 44a (5.0 mg, 15% yield, >99% ee) as a white solid and 44b (5.0 mg, 15% yield, >93% ee) as a white solid.
[1034] 44a ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) 8.32 (dd, J=6.4, 2.9 Hz, 1H), 7.69-7.54 (m, 1H), 7.38-7.20 (m, 2H), 5.97 (s, 1H), 4.45 (s, 1H), 4.07-3.91 (m, 2H), 3.85-3.72 (m, 2H), 3.67-3.56 (m, 1H), 3.49 (s, 3H), 2.97-2.86 (m, 4H), 1.40 (dd, J=12.6, 10.1 Hz, 1H), 1.35-1.25 (m, 5H), 1.18 (q, J=7.2 Hz, 2H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+; R.sub.t=12.98 min.
[1035] 44b ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone): .sup.1H NMR (400 MHz, CD.sub.3OD) 8.31 (dd, J=6.5, 2.9 Hz, 1H), 7.67-7.51 (m, 1H), 7.29 (dd, J=6.1, 3.2 Hz, 2H), 5.97 (s, 1H), 4.44-4.34 (m, 1H), 4.02 (d, J=11.4 Hz, 2H), 3.80 (dd, J=22.8, 7.2 Hz, 2H), 3.60 (s, 1H), 3.49 (s, 3H), 2.95-2.87 (m, 4H), 1.43-1.29 (m, 6H), 1.21-1.12 (m, 2H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+; R.sub.t=16.31 min.
[1036] Alternatively, Example 44b can also be prepared from Int. CC, Isomer 1b.
EXAMPLES 45a and 45b
[1037] ##STR00254##
(R)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone and
[1038] ##STR00255##
(S)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-.SUP.6.-sulfanone
[1039] Synthesis is similar to that described for Example 17. The mixture of diastereomers (300 mg, 0.691 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2, MeOH/CH.sub.3CN (1:1) (0.25% i-PrNH.sub.2)=65:35; Flow rate: 80 g/min; 5 min; Column temperature: 25 C.; Back pressure: 100 bar; Column: Chiral Technologies Chiralcel OX-H, 21250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 45a (94 mg, 31% yield, 95% ee) as a tan solid and 45b (125 mg, 42% yield, 96% ee) as a tan solid.
[1040] 45a ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (600 MHz, DMSO-d.sub.6) 6.85 (s, 1H), 6.65 (s, 1H), 6.00 (s, 2H), 5.90 (s, 1H), 5.02-4.95 (m, 1H), 4.95 (t, J=6.8 Hz, 1H), 4.90-4.83 (m, 3H), 4.39 (s, 1H), 4.04 (d, J=13.2 Hz, 1H), 3.92 (d, J=11.5 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.3 Hz, 1H), 3.59 (d, J=11.3 Hz, 1H), 3.51 (s, 3H), 3.45 (t, J=12.0 Hz, 1H), 3.09 (t, J=12.9 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.26N.sub.6O.sub.4S requires: 434, found: 435 [M+H].sup.+; R.sub.t=3.1 min.
[1041] 45b ((R)-methyl(oxetan-3-yl)-.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-.sup.6-sulfanone): .sup.1H NMR (600 MHz, DMSO-d.sub.6) 6.85 (s, 1H), 6.65 (s, 1H), 6.01 (s, 2H), 5.90 (s, 1H), 4.97 (dt, J=22.9, 6.7 Hz, 2H), 4.87 (d, J=8.1 Hz, 3H), 4.41 (s, 1H), 4.03 (d, J=13.3 Hz, 1H), 3.92 (d, J=10.9 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.4 Hz, 1H), 3.59 (d, J=11.4 Hz, 1H), 3.50 (s, 3H), 3.44 (t, J=11.9 Hz, 1H), 3.09 (t, J=12.3 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.26N.sub.6O.sub.4S requires: 434, found: 435 [M+H].sup.+; R.sub.t=3.4 min.
EXAMPLES 46a and 46b
[1042] ##STR00256##
(R)-cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone and
[1043] ##STR00257##
(S)-cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[1044] 46a ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone); synthesized from Int. CC, Isomer 1a similar to that as described for Example 10: (20 mg, 32% yield, >99% ee) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.73 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.60-7.51 (m, 1H), 7.41 (s, 1H), 5.95 (s, 1H), 4.47 (s, 1H), 4.01 (dd, J=36.7, 10.5 Hz, 2H), 3.75 (d, J=11.1 Hz, 1H), 3.64 (d, J=8.7 Hz, 1H), 3.57-3.44 (m, 4H), 3.15 (t, J=12.7 Hz, 1H), 3.00 (s, 1H), 1.21 (d, J=6.7 Hz, 5H), 1.14-1.01 (m, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; R.sub.t=3.20 min.
[1045] 46b ((R)-cyclopropyl(methyl)-.sup.6-sulfanone or (S)-cyclopropyl(methyl)-.sup.6-sulfanone); synthesized from Int. CC, Isomer 1b similar to that as described for Example 10: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.73 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.59-7.48 (m, 1H), 7.44-7.28 (m, 1H), 5.95 (s, 1H), 4.45 (s, 1H), 4.01 (dd, J=36.7, 10.5 Hz, 2H), 3.75 (d, J=11.5 Hz, 1H), 3.64 (d, J=9.4 Hz, 1H), 3.55 (s, 3H), 3.48 (d, J=11.8 Hz, 1H), 3.16 (s, 1H), 3.02 (s, 1H), 1.20 (d, J=6.7 Hz, 5H), 1.10 (s, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; R.sub.t=2.09 min.
EXAMPLE 47
[1046] ##STR00258##
(R)-((2-(1H-indol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[1047] ##STR00259##
(R)-((2-(1H-indol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[1048] To a solution of indole (43 mg, 0.360 mmol) in DMF (0.75 mL) 0 C. was added NaH (60% wt., 16 mg, 0.394 mmol) and the resulting solution was allowed to slowly warm up to RT and stirred over 15 min. The reaction mixture was added a solution of Int. D (100 mg, 0.328 mmol) in a DMF (0.75 mL) and the reaction mixture was heated to 100 C. and stirred for 16 h. The reaction mixture was cooled to RT, partitioned between water (15 mL) and EtOAc (5 mL), the layers were separated and the aqueous layer was extracted with EtOAc (35 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5-100% EtOAc in hexanes) to afford the title compound (42 mg, 33% yield) as a white solid.
[1049] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.77 (d, J=8.28 Hz, 1H) 8.20 (d, J=3.76 Hz, 1H) 7.62 (d, J=8.03 Hz, 1H) 7.30-7.46 (m, 1H) 7.12-7.27 (m, 1H) 6.64 (d, J=3.51 Hz, 1H) 5.75 (s, 1H) 4.38 (br d, J=8.28 Hz, 1H) 3.95-4.13 (m, 2H) 3.83 (s, 1H) 3.80 (br d, J=3.01 Hz, 1H) 3.59-3.69 (m, 1H) 3.50 (d, J=7.03 Hz, 1H) 3.44 (s, 4H) 3.34 (s, 1H) 1.36 (d, J=7.03 Hz, 3H) 1.23 (t, J=7.03 Hz, 1H) 0.91 (s, 1H); MS (ES.sup.+) C.sub.19H.sub.23N.sub.5O.sub.2S requires: 385, found: 386 [M+H].sup.+.
EXAMPLE 48
[1050] ##STR00260##
(R)-dimethyl((2-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[1051] ##STR00261##
(R)-dimethyl((2-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-.SUP.6.-sulfanone hydrochloride
[1052] A reaction vial was charged with Int. D (50 mg, 0.0165 mmol), 2-methylimidazo[1,2-a]pyridine (33 mg, 0.25 mmol), Pd(OAc).sub.2 (1.8 mg, 0.008 mmol), tricyclohexylphosphonium tetrafluoroborate (6.3 mg, 0.017 mmol), pivalic acid (5.0 mg, 0.05 mmol) and K.sub.2CO.sub.3 (46 mg, 0.33 mmol). The vial was sealed, purged with Ar, DMF (1 mL) was added and the resulting mixture was heated to 110 C. for 1 h. The reaction mixture was cooled to RT, filtered through CELITE, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by flash chromatography (0-10% MeOH in CH.sub.2Cl.sub.2) followed by reverse phase chromatography (Mobile phase: A=0.1% HCO.sub.2H/H.sub.2O, B=0.1% HCO.sub.2H/MeCN; Gradient: B=5-50%; 15 min; Column: Biotage SNAP Ultra C18 30 g, HP-Sphere C18 25 m). The combined fractions were treated with 0.1 M aq. HCl, concentrated under reduced pressure and lyophilized to afford the title compound (26 mg, 36% yield) as a white solid.
[1053] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.23 (dt, J=7.03, 1.00 Hz, 1H) 8.01 (d, J=1.00 Hz, 2H) 7.48-7.56 (m, 1H) 5.96 (s, 1H) 4.33-4.47 (m, 2H) 3.91-3.99 (m, 3H) 3.70-3.81 (m, 2H) 3.60-3.69 (m, 1H) 3.45-3.54 (m, 1H) 3.43 (s, 6H) 3.15 (br d, J=3.76 Hz, 1H) 2.90 (s, 3H) 1.13-1.30 (m, 4H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.
EXAMPLE 49
[1054] ##STR00262##
(R)-6-amino-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinamide
Step 1
[1055] ##STR00263##
(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinic acid
[1056] To a solution of Int. BB (30 mg, 0.063 mmol) in THF (225 L), MeOH (45.0 L) and water (45.0 L) was added LiOH (1.5 mg, 0.063 mmol) and the resulting mixture was stirred at RT for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 20 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (15 mg, 0.026 mmol, 41.3% yield) as a pale yellow solid.
[1057] MS (ES.sup.+) C.sub.21H.sub.30N.sub.6O.sub.4S requires: 462, found: 463 [M+H].sup.+.
Step 2
[1058] ##STR00264##
(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinamide
[1059] To a solution of the product form the previous step (15 mg, 0.026 mmol) in acetonitrile (130 L) were added ammonium bicarbonate (8.2 mg, 0.10 mmol), EDC (9.97 mg, 0.052 mmol), HOBt hydrate (8.0 mg, 0.052 mmol) and DIPEA (14 L, 0.078 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was filtered through a Whatman syringe filter (13 mm, 0.45 m) and directly purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 16 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (12 mg, 80% yield) as a pale yellow solid.
[1060] MS (ES.sup.+) C.sub.21H.sub.31N.sub.7O.sub.3S requires: 461, found: 462 [M+H].sup.+.
Step 3
[1061] ##STR00265##
(R)-6-amino-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)picolinamide
[1062] A solution of the product from the previous step (6.6 mg, 0.011 mmol) in TFA (57 L) was stirred at 65 C. for 24 h. The mixture was cooled to RT, diluted with CH.sub.2Cl.sub.2 (2 mL) and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (4 mg, 55% yield) as a white solid.
[1063] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 8.10 (s, 1H), 7.81 (s, 1H), 6.11 (s, 1H), 4.54 (s, 1H), 4.19 (s, 1H), 4.02 (dd, J=11.4, 3.7 Hz, 1H), 3.82 (d, J=11.6 Hz, 1H), 3.73 (dd, J=11.7, 3.1 Hz, 1H), 3.59 (td, J=12.0, 2.8 Hz, 1H), 3.51 (s, 6H), 3.38-3.27 (m, overlap MeOH, 1H), 1.33 (d, J=6.9 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.23N.sub.7O.sub.3S requires: 405, found: 406 [M+H].sup.+.
EXAMPLE 50
[1064] ##STR00266##
(R)-6-amino-4-(4-((dimethyl(oxo-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-N-ethylpicolinamide
Step 1
[1065] ##STR00267##
(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-N-ethylpicolinamide
[1066] A mixture of Int. BB (30 mg, 0.063 mmol) and ethanamine (2.0 M in THF, 629 L, 1.26 mmol) was stirred at 65 C. for 16 h. Another aliquot of ethanamine (2.0 M THF, 629 L, 1.259 mmol) was added and the mixture was heated at 65 C. for an additional 24 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 20 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (15 mg, 49% yield) as a pale yellow solid.
[1067] MS (ES.sup.+) C.sub.23H.sub.35N.sub.7O.sub.3S requires: 489, found: 490 [M+H].sup.+.
Step 2
[1068] ##STR00268##
(R)-6-amino-4-(4-((dimethyl(oxo)-.SUP.6.-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)-N-ethylpicolinamide
[1069] A solution of the product from the previous step (10 mg, 0.020 mmol) in TFA (102 L) was stirred at 65 C. for 24 h. The mixture was cooled to RT, diluted with CH.sub.2Cl.sub.2 (2 mL) and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (6 mg, 44% yield) as a white solid.
[1070] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 8.02 (s, 1H), 7.71 (s, 1H), 6.13 (s, 1H), 4.56 (s, 1H), 4.21 (s, 1H), 4.03 (dd, J=11.7, 3.8 Hz, 1H), 3.83 (d, J=11.6 Hz, 1H), 3.73 (dd, J=11.6, 3.2 Hz, 1H), 3.59 (td, J=12.0, 2.4 Hz, 2H), 3.51 (s, 6H), 3.46 (q, J=7.3 Hz, 2H), 3.39-3.32 (m, overlap MeOH, 1H), 1.34 (d, J=6.8 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.27N.sub.7O.sub.3S requires: 433, found: 434 [M+H].sup.+.
EXAMPLE 51
[1071] ##STR00269##
(R)-dimethyl((6-(3-methylmorpholino)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[1072] ##STR00270##
(R)-dimethyl((6-(3-methylmorpholino)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[1073] A microwave reaction vial was charged with Int. D (0.10 g, 0.33 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (0.10 g, 0.38 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.030 g, 0.040 mmol) and K.sub.3PO.sub.4 (0.22 g, 1.04 mmol) in dioxane (3 mL) and water (0.8 mL) and the mixture was degassed with a stream of N.sub.2 for five minutes. The vial was sealed and heated at 100 C. for 40 minutes in a microwave reactor. The reaction mixture was cooled to RT, partitioned between EtOAc (20 mL) and brine (20 mL), the layers were separated and the aqueous layer was extracted EtOAc (220 mL). The combined organic layers were dried over MgSO.sup.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (1-8% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (78 mg, 59% yield) as a white solid.
[1074] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.71 (d, J=8.78 Hz, 1H), 8.41 (d, J=6.78 Hz, 1H), 7.19-7.35 (m, 1H), 6.79 (td, J=6.84, 1.38 Hz, 1H), 5.75 (s, 1H), 4.32-4.50 (m, 1H), 3.91-4.14 (m, 2H), 3.74-3.90 (m, 2H), 3.57-3.70 (m, 1H), 3.40 (d, J=7.78 Hz, 6H), 3.29 (td, J=12.74, 3.89 Hz, 1H), 2.87 (s, 3H), 1.33 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.
EXAMPLE 52
[1075] ##STR00271##
(R)-((2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[1076] ##STR00272##
(R)-((2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[1077] To a solution of (R)-dimethyl((6-(3-methylmorpholino)-2-(2-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-4-yl)imino)-.sup.6-sulfanone (synthesis is similar to that described for Example 30, derived from Intermed. FF) (0.081 g, 0.14 mmol) in THF (5 mL) was added HF pyridine, 30% (HF ca. 70%, 1.3 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into sat. aq. NaHCO.sub.3 (50 mL) and stirred vigorously for 15 min. The layers were separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (250 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via reverse phase C18 chromatography (10-100% MeCN in 0.1% TFA/H.sub.2O). The combined fractions were made alkaline by the addition of sat. aq. NaHCO.sub.3 and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (250 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (0.052 g, 88% yield) as a white solid.
[1078] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.32-8.50 (m, 1H), 7.63-7.80 (m, 1H), 7.20-7.36 (m, 2H), 5.74 (s, 1H), 5.14 (s, 2H), 4.12-4.27 (m, 1H), 3.96 (br dd, J=11.42, 3.64 Hz, 1H), 3.81 (br d, J=13.05 Hz, 1H), 3.61-3.77 (m, 2H), 3.51 (td, J=11.92, 3.01 Hz, 1H),3.19-3.36 (m, 8H), 1.27 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.3S requires: 416, found: 417 [M+H].sup.+.
EXAMPLE 53
[1079] ##STR00273##
(R)-((2-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[1080] ##STR00274##
(R)-((2-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-.SUP.6.-sulfanone
[1081] A mixture of Int. D (0.152 g, 0.499 mmol), 2-(fluoromethyl)-1H-benzo[d]imidazole (0.090 g, 0.60 mmol), sodium tert-butoxide (0.086 g, 0.90 mmol) and t-BuBrettPhos Palladacycle G3 (0.021 g, 0.025 mmol) in dioxane (5 mL) was degassed with a stream of N.sub.2 for five minutes and the resulting mixture was heated to 80 C. for 18 h. The reaction mixture was cooled to RT, filtered through CELITE and concentrated under reduced pressure. The residue was purified via silica gel chromatography (10% CH.sub.3CN in CH.sub.2Cl.sub.2) to afford the title compound (102 mg, 49% yield) as a white solid.
[1082] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.40 (d, J=8.03 Hz, 1H), 7.77 (br d, J=7.53 Hz, 1H), 7.23-7.46 (m, 2H), 5.85-6.16 (m, 2H), 5.74 (s, 1H), 4.22 (br d, J=4.52 Hz, 1H), 3.80-4.02 (m, 2H), 3.60-3.79 (m, 2H), 3.52 (td, J=11.92, 3.01 Hz, 1H), 3.14-3.39 (m, 7H), 1.27 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.23FN.sub.6O.sub.2S requires: 418, found: 419 [M+H].sup.+.
EXAMPLE 54
[1083] ##STR00275##
(R)-dimethyl((2-(1-methyl-1H-imidazol-5-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[1084] ##STR00276##
(R)-dimethyl((2-(1-methyl-1H-imidazol-5-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-.SUP.6.-sulfanone
[1085] A solution of Int. D (50 mg, 0.164 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (77 mg, 0.20 mmol) in toluene (820 L) was degassed with N.sub.2 for 1 minute. Pd(Ph.sub.3P).sub.4 (19 mg, 0.016 mmol) was added and the mixture was degassed with N.sub.2 for an additional 30 seconds, and the reaction mixture was heated at 110 C. for 16 h. The reaction mixture was cooled to RT, filtered through CELITE, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=0-30%; 20 min; Column: XBridge C18, 5 m, 19 mm150 mm) to afford the title compound (5.4 mg, 6% yield) as a white solid.
[1086] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 8.88 (s, 1H), 8.12 (s, 1H), 5.97 (s, 1H), 4.42-4.36 (m, 1H), 4.28 (s, 3H), 4.03-3.94 (m, 2H), 3.80 (d, J=11.5 Hz, 1H), 3.71 (dd, J=11.6, 3.2 Hz, 1H), 3.57 (td, J=11.9, 3.1 Hz, 1H), 3.44 (s, 6H), 3.32-3.23 (m, overlap MeOH, 1H), 1.29 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.15H.sub.22N.sub.6O.sub.2S requires: 350, found: 351 [M+H].sup.+.
[1087] The compounds reported in Table 2 were synthesized using the method described for the previously disclosed Examples. The appropriate sulfoximines were prepared as described for Intermediates C.
TABLE-US-00002 TABLE 2 Example compounds 55-125. Ex. Ex Structure IUPAC Name MWt [M + H] Method 55
[1088] The activity of the compounds in Examples 1-125 as ATR inhibitors is illustrated in the following assay. The other compounds listed below, which have not yet been made and/or tested, are predicted to have activity in this assay as well.
TABLE-US-00003 Structure IUPAC Name
ATR/ATRIP Enzymatic Assay
[1089] Human full-length FLAG-TEV-ATR and His6-ATRIP were co-expressed in HEK293 cells. The cell pellet (20 g) was harvested and lysed in 100 mL of lysis buffer (20 mM Tris-HCl pH 7.5 at room temperature, 137 mM NaCl, 10% glycerol, 1 mM DTT, 1% (v/v) Tween-20, 0.1% (v/v) NP-40, complete protease inhibitor cocktail tablets, phosphatase inhibitor cocktail tablets, 2 mM MgCl.sub.2, 0.2 mM EDTA, and 1 mM ATP). After sonication and centrifugation, the supernatant was incubated at 4 C. for 3 hours with 1 mL of anti-FLAG resin (Sigma catalog # A2220) that had been pre-equilibrated in buffer A (20 mM Tris-HCl pH 7.5 at room temperature, 137 mM NaCl, 10% glycerol, 1 mM DTT, 2 mM MgCl.sub.2, and 0.2 mM EDTA). The sample was loaded into a column, and then washed with buffer A three times. Protein was subsequently eluted with 2 ml of buffer B (buffer A+200 m/ml 3FLAG peptide).
[1090] The ability of new chemical matter to inhibit the ATR catalytic activity in this ATR/ATRIP complex was assessed using a Caliper-based assay. A 2 enzyme solution (i.e., 4 nM enzyme) was prepared using 1 Kinase Reaction Buffer (25 mM HEPES pH 8, 0.0055% Brij-35, 10 mM MnCl.sub.2, and 1 mM DTT). A 2 peptide solution was then prepared consisting of 10 uM FAM-labeled RAD17 peptide (GL Biochem, catalog #524315) in 1 Kinase Reaction Buffer supplemented with 2 M ATP. 10 L of the 2 enzyme solution was transferred to an assay plate containing 60 nL of test compound (from a 3 serial dilution) in 100% DMSO. Following a 30 minute incubation at 28 C., 10 L of the 2 peptide solution was then transferred to the same assay plate. The reaction was allowed to incubate at 28 C. for 6 hours. After adding 30 L of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating-3 Reagent (PerkinElmer, catalog # PN760050), and 50 mM EDTA), data were collected on a Caliper instrument. Conversion values were converted to inhibition values via the following equation: % inhibition=(maxconversion)/(maxmin)*100, whereby max corresponds to the DMSO control and min corresponds to the low control. IC.sub.50 values were calculated using the following equation in XLFit: Y=Bottom+(Top-Bottom)/1+(IC.sub.50/X){circumflex over ()}HillSlope).
pCHK1 Cellular Assay
[1091] Inhibitors of ATR kinase are effective at inhibiting the ATR-driven phosphorylation of the downstream target Chk1 kinase at Serine 345, following the addition of 4-nitroquinoline N-oxide, a chemical used to induce DNA damage. Cellular IC.sub.50 for the inhibitors of ATR described herein were measured in HT-29 colorectal adenocarcinoma cells. HT-29 cells were routinely maintained in McCoy's 5A media (ATCC Catalog #30-2007) supplemented with 10% fetal bovine serum (Sigma Catalog # F2442) and 1 Penicillin-Streptomycin (Gibco Catalog #15140-122) using a humidified incubator (37 C., 5% CO.sub.2, and ambient O.sub.2). In preparation for the CHK1 (p-Ser345) ALPHASCREEN SUREFIRE assay, cells were harvested and resuspended in McCoy's 5A media supplemented with 10% fetal bovine serum and 1 Penicillin-Streptomycin. Cells were seeded onto a 384-well black CELLSTAR Tissue Culture Plate (VWR Catalog #89085-314) at a density of 13,000 cells/well in a volume of 40 L. The microplate was incubated overnight (approximately 20 hours) at 37 C. with 5% CO.sub.2 and ambient O.sub.2. Stock solutions of the test compounds were prepared in 100% DMSO (Sigma, Catalog # D2650) and serially diluted 1:3 using 100% DMSO. Compounds were additionally diluted 1:33 in culture medium, and 10 L/well were transferred to the tissue culture plate. Following the compound addition the microplate was incubated at 37 C. for 90 minutes. 10 L of 4-nitroquinoline N-oxide (Sigma Aldrich Catalog # N8141-1G) diluted in media (final concentration 12 uM) were added to the tissue culture plate followed by a 120 minute incubation at 37 C. The cells were then washed with PBS and lysed using 10 L/well SUREFIRE Kit lysis buffer diluted to 1 in water (PerkinElmer Catalog # TGRCHK1S50K), with mixing on an orbital shaker at 500 rpm for 20 min at RT. Lysates were frozen at 20 C. overnight.
[1092] 4 L/well of lysate was then transferred from the tissue culture plate to a 384-well, white, low volume, PROXIPLATE (PerkinElmer Catalog #600828). 5 L/well of the acceptor bead solution, prepared by diluting SUREFIRE Kit activation buffer (PerkinElmer Catalog # TGRCHK1S50K) and ALPHASCREEN Protein A acceptor beads (PerkinElmer Catalog #6760617R) in SUREFIRE Kit reaction buffer (PerkinElmer Catalog # TGRCHK1S50K), were added to the lysates under subdued light and incubated at room temperature for 120 min. 2 uL/well of the donor bead solution, prepared by diluting ALPHASCREEN Streptavidin donor beads (PerkinElmer Catalog #6760617R) in SUREFIRE Kit dilution buffer (PerkinElmer Catalog # TGRCHK1S50K), were added under subdued light and incubated at room temperature for an addition 120 minutes. The pCHK1 ALPHASCREEN signal was measured using an ENVISION plate reader (PerkinElmer). IC.sub.50 values were calculated using a four-parameter logistic curve fit using Genedata Screener software. Percent of control for each compound concentration was calculated by the following formula: 100*(Compound-Min)/(Max-Min) where Max is the high control, DMSO, and Min is the low control, 5 uM ATR inhibitor.
TABLE-US-00004 TABLE 3 ATR/ATRIP Enzyme IC.sub.50 values ATR- ATRIP pCHK1 Ex IC.sub.50, nM IC.sub.50 (nM) 1 1 46 2 5 64 3 2 44 4 8 86 5 3 48 6 N.A. 212 7 4 77 8 N.A. 167 9 N.A. 136 10 26 909 11 7 17 12 4 56 13 104 73 14 122 463 15 182 335 16 3 20 17a 4 38 17b 7 61 18a 258 408 18b 71 49 19 8 131 20 67 798 21 21 311 22 77 669 23 31 1718 24 36 1986 25 22 39 26 81 131 27 405 1855 28 246 575 29 10 92 30 3 47 31 1.6 14 32 259 10000 33 47 1617 34 3 895 35 195 1177 36 50 4668 37 306 87 38a 0.7 56 38b 1.4 563 39a 48 26 39b 525 1356 40a 0.8 402 40b 0.3 30 41a 15 945 41b 0.8 28 42a 31 25 42b 284 940 43a 153 44 43b 387 399 44a 6 902 44b 0.4 18 45a 110 65 45b 419 431 46a 8 179 46b 1 8 47 3 1372 48 34 263 49 159 7586 50 486 8232 51 55 439 52 0.9 44 53 0.5 14 54 978 3033 55 4 61 56 2 27 57 15 202 58 15 175 59 21 183 60 4 41 61 3 77 62 5 89 63 4 169 64 2 68 65 20 372 66 207 198 67 3 168 68 244 1448 69 59 676 70 3 48 71 2 138 72 23 4414 73 27 2317 74 73 6099 75 63 1668 76 17 408 77 135 3385 78 5 22 79 233 6070 80 6 720 81 353 219 82 134 670 83 45 1569 84 158 1828 85 20 7684 86 0.4 28 87 316 164 88 2 58 89 435 653 90 1072 133 91 334 228 92 4 46 93 115 48 94 326 10000 95 0.9 20 96 3 57 97 208 776 98 117 252 99 3 99 100 3 26 101 17 158 102 10 904 103 218 1217 104 88 244 105 14 757 106 3 351 107 7 339 108 2 110 109 2 341 110 143 4326 111 123 273 112 205 4888 113 72 51 114 480 1113 115 307 3623 116 105 58 117 277 564 118 158 136 119 17 175 120 26 250 121 24 133 122 594 6478 123 821 >10000 N.A. = not available
Anti-Tumor Effects in Mouse Xenografts
[1093] The effect of compounds 1, 39a, 30, and 18b on tumor growth was assessed in a LoVo (human colorectal) mouse xenograft model. Female CD1 nude mice were injected subcutaneously in the right flank with a suspension of LoVo cells (1 million cells/100 ul PBS+100 ul Matrigel; cells purchased from ATCC and cultured following ATCC's guideline). After implantation, tumor volume (TV) was measured weekly and mice bearing tumors with volumes between 200-250 mm.sup.3 were randomized into treatment groups of 5 to 10 mice each. Mice were dosed by oral gavage, once daily for 21 days with either vehicle or 1, 39a, 30, and 18b at the doses reported in Table 4. The doses were scaled to the body weights (BW) of individual animals at a dosing volume of 10 mL/Kg. Throughout the duration of study tumor growth was assessed by caliper measurement and treatment response was determined by percent tumor growth inhibition (% TGI; calculated as TGI %=100([TV.sub.end_treatTV.sub.start-treat]/[TV.sub.end-cntrlTV.sub.tart-cntrl]; where TV.sub.end-treat, TV.sub.start-treat, TV.sub.end-cntrl-and TV.sub.tart-cntrl are the median tumor volumes for the compound treated and control groups respectively at the end and at the start of the study. Mouse body weight was measured bi-weekly, and reported as percentage of mean BW change from Day 1. Significant tumor growth inhibition was observed for all the compounds, as shown in Table 4, with no body weight loss.
TABLE-US-00005 TABLE 4 Anti-tumor effect in LoVo xenograft model in CD1 nude mice Tumor Growth Body Weight Inhibition % Change % Ex. Dose (mg/Kg) (TGI %; day 21) (BW %; day 21) 1 100 96* +9.8 39a 25 59* +0.9 30 10 73* +7.3 18b 10 81* +0.4 *= p < 0.05 **, two-tailed test;
[1094] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.
[1095] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions.