NZ731504B2 - Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines - Google Patents
Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines Download PDFInfo
- Publication number
- NZ731504B2 NZ731504B2 NZ731504A NZ73150415A NZ731504B2 NZ 731504 B2 NZ731504 B2 NZ 731504B2 NZ 731504 A NZ731504 A NZ 731504A NZ 73150415 A NZ73150415 A NZ 73150415A NZ 731504 B2 NZ731504 B2 NZ 731504B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- difluoromethyl
- triazinyl
- pyridinamine
- compound
- dimethylmorpholinyl
- Prior art date
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- ANDIJFDISUBYSA-UHFFFAOYSA-N 3-(difluoromethyl)pyridin-2-amine Chemical class NC1=NC=CC=C1C(F)F ANDIJFDISUBYSA-UHFFFAOYSA-N 0.000 title claims description 37
- SUVMSNKJNMLRRL-UHFFFAOYSA-N 4-(difluoromethyl)pyrimidin-2-amine Chemical class NC1=NC=CC(C(F)F)=N1 SUVMSNKJNMLRRL-UHFFFAOYSA-N 0.000 title claims description 4
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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Abstract
The invention relates to novel phosphoinositide 3-kinase (PI3K),mammalian target of rapamycin (mTOR)and PI3K-related kinase(PIKKs)inhibitor compounds of formula (I), wherein X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases. , either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.
Description
WO 75130
Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines
Field of the Invention
The invention relates to new difluoromethyI-aminopyridyl- and difluoromethyl-
aminopyrimidinyI-substituted triazines and pyrimidines as therapeutic agents and
diagnostic probes useful for modulating ar activities such as signal transduction,
proliferation, differentiation, cell death, migration, and control, release and action of
inflammatory mediators, chemokines and cytokines. The compounds of the invention
modulate kinase activities, in particular those of phosphoinositide 3-kinase (PI3K),
oinositide se (PI4K), mammalian target of rapamycin , Vps34 and
PI3K-related s (PIKKs).
Background of the ion
Protein kinases participate in the signaling events and control ar activation, growth,
differentiation, survival and migration in response to extracellular mediators or stimuli
including growth factors, nes or chemokines. In general, these kinases are classified
in two , those that preferentially phosphorylate tyrosine residues and those that
preferentially phosphorylate serine and/or threonine residues. Tyrosine kinases include
membrane-spanning growth factor receptors, for example the epidermal growth factor
receptor (EGFR) and cytosolic non-receptor kinases including Src family kinases, the Syk
family kinases and the Tec family s.
Increased protein kinase ties are involved in many diseases including cancer,
metabolic diseases, immunological diseases and inflammatory disorders. These can be
caused either directly or indirectly by the failure of control mechanisms due to mutation(s),
overexpression or inappropriate control of enzyme activity.
Protein tyrosine kinases — both receptor tyrosine kinases and non-receptor kinases — are
essential for the activation and proliferation of cells of the immune system. Among the
earliest detectable events upon immunoreceptor tion in mast cells, T cells and B
cells is the stimulation of non-receptor tyrosine kinases.
Phosphoinositide 3-kinases (PI3Ks) were early on identified as lipid kinases associated
with viral nes an et al., Nature 315:239—242 (1985)], and for the last 20
years, the connection between cancer and PI3K has been further substantiated [Wymann
WO 75130
etal., Curr. Opin. Cell Biol. 17:141-149 (2005)]. P|3Ks have since been recognized to
modulate a wide range of cellular activities, and to be central to the growth and metabolic
control. Genetically modified mice targeting the P|3K pathway, and the ation of
human hereditary disease like Cowden's syndrome, tuberous sclerosis, ataxia
telangiectasia, X-linked myotubular myopathy and t-Marie-Tooth neuropathy, have
provided further insight into the cellular and systemic role of phosphoinositide ing.
Deregulation of phosphoinositide levels, and in particular the product of class I Pl3Ks,
Ptdlns (3,4,5)P3, is involved in the pathogenesis of cancer, chronic inflammation, allergy,
lic disease, diabetes and cardiovascular problems.
P|3Ks are a family of enzymes, which phosphorylate the 3'-OH position of the inositol ring
of phosphoinositides. They have been divided into three classes on the basis of structural
features and in vitro lipid substrate icity [Marone et al., Biochimica et Biophysica
Acta 1784:159—185 (2008)]. Class | P|3Ks form heterodimers, which consist of one of the
four closely related catalytic ts of approx. 110 kDa, and an ated regulatory
subunit belonging to two ct families. In vitro they are capable to t Ptdlns to
PtdlnsP, PtdlnsP to (3,4)P2, and Ptdlns(4,5)P2 to Ptdlns(3,4,5)P3, but the in
vivo substrate is Ptdlns(4,5)P2 [Cantley eta/., Science 296:1655-1657 (2002)]. Class |
P|3Ks are activated by a large variety of cell-surface receptors, comprising growth factor
ors as well as G protein-coupled receptors.
Class II P|3Ks are capable to phosphorylate Ptdlns and PtdlnsP in vitro, but their
relevant in vivo substrates are still under investigation. This class of large (170-200 kDa)
enzymes has three members, all characterized by a C-terminal C2 homology domain. No
adaptor molecules for class II P|3Ks have been identified so far. Class III P|3Ks are solely
able to phosphorylate Ptdlns, and thus generate only PtdlnsP. The single member of
this class is Vps34, of which the S. cerevisiae Vps34p (vacuolar protein sorting mutant 34
protein) is the prototype, and has been shown to play an essential role in trafficking of
newly synthesized proteins from the Golgi to the yeast vacuole, an organelle equivalent to
lysosomes in mammals [Schu etal., Science 260:88—91 (1993)].
Phosphoinositide 4-kinases (Pl4Ks) phosphorylate the 4'-OH on of the inositol ring of
Ptdlns, and thereby generate PtdlnsP. This lipid can then be further phosphorylated by
P ses to generate Ptdlns 2, which is the main source for
phospholipase C and PI3K signaling at the plasma membrane. Four P|4Ks isoforms are
known: P|4Kllcx and B and P|4Klllcx and B. The P|4Kllls are most closely related to Pl3Ks.
The class of Pl3K-related proteins, referred to as class IV Pl3Ks, consists of high
molecular weight enzymes with a catalytic core similar to Pl3Ks and P|4Ks and include
the mammalian target of rapamycin (mTOR, also known as FRAP), DNA-dependent
protein kinase (DNA-PKcs), the ataxia telangiectasia mutated gene product (ATM), ataxia
iectasia related (ATR), SMG-1 and transformation/transcription domain-associated
protein (TRRAP). The first five members are active protein serine-threonine kinases that
are involved in cell growth control and genome/transcriptome surveillance [Marone et al.,
Biochimica et Biophysica Acta 1784:159—185 (2008)]. DNA-PKcs, ATM, ATR and SMG-1
are involved in DNA damage responses. The only active kinase not involved in DNA
damage is mTOR, which is regulated by growth factors and nutrient availability, and
coordinates protein synthesis, cell growth and proliferation. Target of rapamycin (mTOR)
complexes 1 and 2 integrate growth factor signaling (via KB and the Ras/MAPK
cascade), energy status (LKB1 and AMPK) and nutrient detection. TOR is vely
ted by PKB/Akt, which phosphorylates the negative regulator TSC2 in the tuberous
sclerosis complex (TSC), resulting in activation of the GTPase Rheb and mTOR. In
parallel, mTOR stimulates translation of ribosomal proteins and ore ribosome
biogenesis via the activation [Wullschleger etal., Cell 124:471 (2006)]. Rapamycin and its
derivatives, RAD001 and CCl-779, bind to FKBP12, and the complex blocks mTOR
complex 1 (mTORC1) activity very selectively. Various clinical trials were ted using
rapamycin and derivatives, mostly in patients with tumors displaying elevated P|3K
signaling and hyperactive mTOR.
The P|3K pathway is a key signaling transduction cascade controlling the regulation of cell
growth, proliferation, survival as well as cell migration. Pl3Ks are activated by a wide
variety of ent stimuli including growth s, inflammatory ors, es,
neurotransmitters, and immunoglobulins and antigens [Wymann et al., Trends Pharmacol.
Sci. -376 (2003)]. The class IA P|3K isoforms Pl3Ko, B and 6 are all bound to one
of the p85/p55/p50 regulatory subunits, which all harbor two 8H2 s that bind with
high ty to phosphorylated Tyr-X-X-Met motifs. These motifs are present in activated
growth factor receptors, their substrates and numerous adaptor proteins. As described
above, activation of the Pl3K/PKB signaling e has a positive effect on cell growth,
survival and proliferation. Constitutive up-regulation of PI3K signaling can have a
deleterious effect on cells leading to uncontrolled proliferation, ed migration and
adhesion-independent growth. These events favor not only the formation of malignant
, but also the development of inflammatory and autoimmune disease.
The patent applications WO2010/052569, WO2007/084786 and WO2008/098058
describe certain analogous triazines and pyrimidines derivatives having PI3K and mTOR
inhibiting properties, and their use as pharmaceuticals.
Summary of the Invention
In one aspect, there is ed a compound of formula (I),
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N;
Y is N or CH;
R1 and R2 are independently of each other
(i) a linyl of a (II)
R3 R4
(II)
n the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form er a bivalent residue –
R5R6– selected from -CH2-O-CH2-, -CH2-NH-CH2-, or C1-C3alkylene optionally
substituted with 1 to 4 F, or any of the structures
wherein the arrows denote the bonds in formula (II); or
(ii) a saturated 5- to 6-membered heterocyclic ring Z containing 1 to 2
heteroatoms independently selected from N, O and S, optionally substituted
by 1 to 3 R9; wherein R9 is independently at each occurrence halogen, -OH,
07_1 (GHMatters) P42872NZ00
C1-C3alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, lkoxy, C1-
C2alkoxyC1-C3alkyl, ycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9
substituents form together a bivalent residue –R10R11– selected from -CH2-OCH2-
, -O-CH2CH2-O-, or C1-C3alkylene optionally substituted with 1 to 4 F;
with the proviso that at least one of R1 and R2 is a morpholinyl of formula II;
and tautomers, es and pharmaceutically acceptable salts thereof.
In another aspect, there is provided a pharmaceutical composition comprising a
compound of formula (I) as defined herein and a pharmaceutically acceptable carrier.
In another aspect, there is provided a use of a compound of formula (I) as defined herein
in the preparation of a medicament for the treatment or prevention of a disease or
condition ted by PI3Ks and/or mTOR and/or PIKKs in a human.
The invention relates in a first aspect to difluoromethyl-substituted heteroaromatic
compounds of formula (I),
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N;
Y is N or CH;
R1 and R2 are ndently of each other
(i) a linyl of formula (II)
R3 R4
(II)
wherein the arrow denotes the bond in formula (I); and
n R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue –
17511707_1 (GHMatters) P42872NZ00
4b followed by page 5
R5R6– selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
n the arrows denote the bonds in formula (II);
(ii) phenyl optionally substituted with 1 to3 R7, wherein R7 is ndently at each
occurrence halogen, -OH, C1-C3alkyl optionally substituted with one or two OH,
17511707_1 (GHMatters) P42872NZ00
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3)2;
(iii) a 5- to 6-membered heteroaryl ring W containing one to four heteroatoms
ndently selected from N, O and S, optionally substituted by 1 to 3 R8,
wherein R8 is ndently at each occurrence halogen, -OH, lkyl
ally substituted with one or two OH, C1-szluoroalkyl, lkoxy, C1-
CzalkoxyC1-Cgalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3)2;
(W) a saturated 4- to 6-membered heterocyclic ring Z containing 1 to 3 atoms
independently selected from N, O and S, optionally substituted by 1 to 3 R9;
wherein R9 is independently at each occurrence halogen, -OH, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
xyC1-Cgalkyl, ycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9
substituents form together a bivalent residue —R10R11— selected from C1-
Cgalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CHZCH2-O-;
(V) OR”, wherein R12 is C1-Cgalkyl, C1-Cshaloalkyl, C1-Csalkoxy, ycloalkyl,
C1-Czalkylenecg-Cscycloalkyl; Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-
P represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3
heteroatoms ndently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
Cgalkyl optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Q represents 5- to ered heteroaryl
ring ning one to four heteroatoms independently selected from N, O and
S, optionally substituted by 1 to 3 R14, wherein R14 is independently at each
occurrence halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH,
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3); or
(Vi) NR15R16; wherein R15 and R16 are independently of each other H, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl; Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-P
represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3
heteroatoms independently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
Cgalkyl optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or ; Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Q represents 5- to 6-membered heteroaryl
2015/076192
ring ning one to four heteroatoms independently selected from N, O and
S, optionally tuted by 1 to 3 R14, wherein R14 is independently at each
occurrence halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH,
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or ;
with the proviso that at least one of R1 and R2 is a morpholinyl of formula II;
and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts
thereof.
In further aspects, the invention relates to pharmaceutical compositions comprising a
compound of formula (I) as defined hereinbefore, and to methods of preventing or treating
a disease or er modulated by Pl3Ks, mTOR and PlKKs, in particular treating a
hyperproliferative disorder, comprising administering to a mammal in need of such
treatment an effective amount of a compound of formula (I) as defined hereinbefore. An
additional aspect of the ion is the use of a compound of formula (I) as defined
hereinbefore for the treatment or prevention of a disease or ion modulated by
Pl3Ks, mTOR and PlKKs in a mammal, and the use of a compound of formula (I) as
defined hereinbefore in the preparation of a medicament for the treatment or prevention of
a disease or condition ted by Pl3Ks, mTOR and PlKKs, in a mammal.
ln again further aspects, the ion relates to the use of an effective amount of
compounds of formula (I) as defined hereinbefore in combination with standard treatment,
such as chemotherapy, herapy, targeted therapy or immunotherapy of a disease or
disorder modulated by Pl3Ks, mTOR and PlKKs, in particular hyperproliferative disorders.
Further the invention relates to the synthesis of compounds of a (I) as defined
hereinbefore including tautomers, solvates, intermediates, prodrugs and salts of said
compounds.
Further aspects and embodiments of the present invention will be become apparent as
this description continues.
Detailed Description of the Invention
Reference will now be made in detail to the presented and further aspects and the
presented and further ments of the ion, examples of which are illustrated in
the accompanying structures and formulas. While the invention will be described in
conjunction with the enumerated embodiments, it will be understood that they are not
intended to limit the invention to those embodiments. On the contrary, the invention is
intended to cover all alternatives, cations, and equivalents which may be ed
within the scope of the present invention as defined by the aspects of the present
invention and, in particular the . One skilled in the art will recognize many methods
and materials similar or lent to those described herein, which could be used in the
practice of the present invention. The present invention is in no way limited to the methods
and materials herein described.
Definitions
The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or
preventative es, wherein the object is to prevent or slow down (lessen) an
undesired pathological change or disorder, such as the development or spread of cancer.
For purpose of this ion, beneficial or d clinical results include, but are not
limited to, alleviation of ms, diminishment of extent of disease, stabilized (i.e., not
worsening) state of disease, delay or slowing of disease progression, amelioration or
palliation of the disease state, and remission (whether partial or , r detectable
or undetectable. "Treatment" can also mean prolonging survival as compared to expected
survival if not receiving treatment. Those in need of treatment include those already with
the condition or disorder as well as those prone to have the condition or disorder or those
in which the condition or er is to be prevented.
The phrase "effective amount" means an amount of a compound of the present invention
that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates,
rates, or eliminates one or more symptoms of the particular disease, condition, or
disorder, or (iii) prevents or delays the onset of one or more symptoms of the ular
disease, condition, or disorder described herein. In the case of cancer, the effective
amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit
(i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral
organs; t (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to
some extent, tumor growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. To the extent the drug may prevent growth and/or kill existing
cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be
measured, for example, by assessing the time to disease ssion (TIP) and/or
determining the response rate (RR).
The terms "cancer" and "cancerous" refer to or describe the physiological condition in
mammals that is typically characterized by unregulated cell growth. A "tumor" comprises
one or more cancerous cells. Examples of cancer include, but are not limited to,
carcinoma, lymphoma, blastoma, sarcoma, and leukaemia or lymphoid malignancies.
More particular examples of such cancers include squamous cell cancer (e.g., epithelial
squamous cell ), lung cancer including small-cell lung cancer, non-small cell lung
cancer ("NSCLC"), arcinoma of the lung and squamous carcinoma of the lung,
cancer of the peritoneum, hepatocellular cancer, gastric or h cancer including
intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer,
liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer,
colorectal cancer, trial or uterine carcinoma, salivary gland oma, kidney or
renal cancer, prostate , vulval cancer, thyroid cancer, hepatic carcinoma, anal
carcinoma, penile carcinoma, bile duct cancer, mantle cell lymphoma, CNS ma,
chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, as well as head and neck
cancer.
A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer.
Examples of known chemotherapeutic agents include trastuzumab, pertuzumab, erlotinib
(TARCEVA®, ech/Roche/OSI Pharm.), bortezomib (VELCADE®, Millennium
Pharm.), fulvestrant (FASLODEX®, AstraZeneca), b (SUTENT®, Pfizer/Sugen),
letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate
(VATALAN|B®, Novartis), oxaliplatin (ELOXAT|N®, Sanofi), 5-FU (5-fluorouracil),
leucovorin, rapamycin (Sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®,
GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (NEXAVAR, Bayer
Labs), and gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as
thiotepa and CYTOXAN® phosphamide; alkyl sulfonates such as busulfan,
improsulfan and piposulfan; aziridines such as benzodopa, uone, meturedopa, and
a; nimines and melamines including altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine;
acetogenins; a camptothecin (including the tic analog topotecan); bryostatin;
tatin; 5 (including its adozelesin, carzelesin and bizelesin synthetic analogs);
cryptophycins; dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and
CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards
such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin,
phenesterine, mustine, trofosfamide, uracil mustard; nitrosureas such as
carmustine, chlorozotocin, fotemustine, ine, nimustine, and ranimnustine;
antibiotics such as the enediyne antibiotics (e.g., ca|icheamicin, especially ca|icheamicin
gammal 1 and ca|icheamicin omegal 1; dynemicin, ing dynemicin A;
phonates, such as c|odronate; an micin; as well as neocarzinostatin
chromophore and related chromoprotein enediyne antibiotic chromophores,
aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin,
cin, carminomycin, carzinophillin, chromomycinis, dactinomycin, daunorubicin,
detorubicin, 6-diazoloxo-L-norleucine, ADRIAMYC|N® (doxorubicin), morpholino-
doxorubicin, cyanomorpholino-doxorubicin, olino-doxorubicin and
deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as
mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin,
puromycin, quelamycin, rodorubicin, onigrin, streptozocin, tubercidin, ubenimex,
zinostatin, cin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogs such as denopterin, methotrexate, pteropterin, rexate; purine
analogs such as abine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine
analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, bine,
dideoxyuridine, doxifluridine, enocitabine, idine; androgens such as ca|usterone,
tanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such
as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine;
bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine;
elliptinium acetate; an epothilone; etoglucid; gallium nitrate; yurea; lentinan;
|onidainine; maytansinoids such as maytansine and ansamitocins; azone;
mitoxantrone; mopidanmol; rine; pentostatin; phenamet; pirarubicin; losoxantrone;
podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex;
ne; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone;
trichothecenes; urethane; indesine; dacarbazine; mannomustine; mitobronitol; mito|acto|;
pipobroman; gacytosine; arabinoside; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers
Squibb), ABRAXANET'V' (Cremophor—free), albumin-engineered nanoparticle formulations
of paclitaxel, and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); mbucil;
GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum
analogs such as cisp|atin and carboplatin; vinblastine; etoposide; ifosfamide;
mitoxantrone; vincristine; NAVELBI NE® (vinorelbine); novantrone; teniposide;
edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); onate; CP-11;
topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as
retinoic acid; and pharmaceutically acceptable salts; acids and derivatives of any of the
above.
Also included in the definition of "chemotherapeutic agent" are: (i) anti-hormonal agents
that act to regulate or inhibit hormone action on tumors such as anti-estrogens and
selective receptor modulators (SERMs), including, for example, tamoxifen (including
NOLVADEX®; tamoxifen citrate), fene, droloxifene, and ON® (toremifine
citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates
estrogen production in the adrenal glands, such as, for example, 4(5)—imidazoles,
MEGASE® trol acetate); AROMAS|N® stane; Pfizer), formestanie,
fadrazole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and EX®
(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide; (iv) protein
kinase inhibitors; (v) lipid kinase inhibitors; (vi) nse oligonucleotides, particularly
those which inhibit expression of genes in signaling pathways implicated in aberrant cell
proliferation, such as, for example, PKC-alpha, Rafl and H-Ras; (vii) mes such as
VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii)
vaccines such as gene therapy vaccines, for e, ALLOVECT|N®, LEUVECT|N®,
and ; PROLEUK|N® rll-2; a topoisomerase 1 inhibitor such as LURTOTECANE®;
ABAREL|X® rmRH; (ix) ngiogenic agents such as bevacizumab (AVAST|N®,
Genentech/Roche); and (x) pharmaceutically acceptable salts, acids and derivatives of
any of the above.
The term "prodrug" as used in this application refers to a precursor or derivative form of a
compound of the invention that may have improved properties such as better solubility,
reduced cytotoxicity or increased bioavailability compared to the parent compound or drug
and is capable of being activated or converted into the more active parent form. The
gs of this ion include, but are not limited to, derivatives of the amino group
connected to the pyridine or pyrimidine nucleus in which one or two hydrogens are
replaced by a suitable substituent, or derivatives of the ring amino function if R2 is
piperazinyl. Examples of such prodrugs are compounds acylated by an amino acid
selected from the 20 most often occurring l L-alpha-amino acids, ed by a
dipeptide such as L-Ala-L-Ala, by carbonic acid, ic acid or phosphoric acid, as well
as pharmaceutically acceptable salts thereof.
A "metabolite" is a product produced through metabolism in the body of a ied
compound or salt thereof. Metabolites of a compound may be identified using routine
ques known in the art and their activities determined using tests such as those
described . Such ts may result for example from the oxidation, reduction,
ysis, amidation, deamidation, esterification, deesterification, enzymatic ge,
and the like, of the administered nd. In particular, compounds of formula (I) as
defined hereinbefore, which are oxygenated or hydroxylated at any one position in the
morpholine, piperazine or thiomorpholine ring R1 and/or R2 are considered metabolites.
Further metabolites considered are thiomorpholine S—oxides and thiomorpholine 8,8-
dioxides. Accordingly, the invention is also directed to metabolites of compounds of the
ion, including compounds produced by a process comprising contacting a
compound of this invention with a mammal for a period of time sufficient to yield a
metabolic product thereof.
A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or
surfactants, which is useful for ry of a drug (such as the P|3K and mTOR kinase
inhibitors disclosed herein and, optionally, a chemotherapeutic agent) to a mammal. The
components of the liposome are commonly arranged in a bilayer formation, similar to the
lipid arrangement of biological membranes.
The term "chiral" refers to molecules, which have the property of perimposability of
the mirror image partner, while the term al" refers to molecules, which are
superimposable on their mirror image partner.
The term "stereoisomers" refers to compounds, which have identical chemical
constitution, but differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a isomer with two or more centers of chirality in which the
compounds are not mirror images of one another. Diastereomers have different physical
properties, e.g. g points, boiling points, spectral properties, and chemical and
biological vities. Mixtures of diastereomers may be separated under high resolution
analytical procedures such as electrophoresis and chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable
mirror images of one another.
Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed.,
McRaw—Hiff Dictionary of Chemical Terms (1984), McGraw—Hill Book Company, New
York; and Eliel, E. and Wilen, 8., "Stereochemistry of Organic Compounds", John Wiley &
Sons, Inc, New York, 1994. The nds of the ion may contain asymmetric or
chiral centers, and therefore exist in ent stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including but not limited to,
reomers, enantiomers and atropisomers, as well as mixtures thereof such as
racemic mixtures, form part of the present invention. Many c compounds exist in
optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
In describing an optically active compound, the prefixes D and L, or R and S, are used to
denote the absolute configuration of the molecule about its chiral center(s). The prefixes d
and | or (+) and (-) are employed to designate the sign of rotation of plane-polarized light
by the compound, with (—) or | meaning that the nd is levorotatory. A compound
prefixed with (+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of one another. A specific
stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is
often called an enantiomeric or a scalemic mixture. A 50:50 mixture of enantiomers is
referred to as a racemic mixture or a racemate. The term "tautomer" or meric form"
refers to structural isomers of different energies, which are onvertible via a low
energy barrier. For example, proton tautomers include interconversions via migration of a
proton, such as keto-enol and imine-enamine isomerizations.
The phrase aceutically acceptable salt" as used herein, refers to pharmaceutically
acceptable c or nic salts of a compound of the ion, in particular acid
addition salts. Exemplary salts include, but are not limited to, sulfate, citrate, acetate,
oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, , tannate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, ate, glucuronate,
saccharate, formate, benzoate, glutamate, methanesulfonate (mesylate), ethane-
sulfonate, benzenesulfonate, enesulfonate, and pamoate salts. A pharmaceutically
acceptable salt may involve the inclusion of another molecule such as an acetate ion, a
succinate ion or other counter ion. The counter ion may be any organic or inorganic
moiety that stabilizes the charge on the parent nd. Furthermore, a
pharmaceutically acceptable salt may have more than one d atom in its structure.
lnstances where multiple charged atoms are part of the pharmaceutically acceptable salt
can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one
or more charged atoms and/or one or more counter ion.
If the nd of the invention is a base, the desired pharmaceutically acceptable salt
may be prepared by any suitable method available in the art, for example, treatment of
the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic
acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid,
fumaric acid, malonic acid, c acid, oxalic acid, glycolic acid, salicylic acid, a
pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid,
such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid,
an aromatic acid, such as c acid or cinnamic acid, a sulfonic acid, such as p-
toluenesulfonic acid or ethanesulfonic acid, or the like.
The phrase "pharmaceutically acceptable" indicates that the substance or ition
must be compatible ally and/or toxicologically, with the other ingredients
comprising a formulation, and/or the mammal being treated therewith.
A "solvate" refers to an association or x of one or more solvent molecules and a
compound of the invention. Examples of solvents that form solvates include, but are not
limited to, water, isopropanol, ethanol, methanol, dimethyl ide (DMSO), ethyl
acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where
the solvent molecule is water.
The term cting group" refers to a substituent that is ly employed to block or
protect a particular functionality during the reaction of other functional groups on the
compound. For example, an "amino-protecting group" is a substituent ed to an
amino group that blocks or protects the amino functionality in the compound. Suitable
amino-protecting groups include acetyl, trifluoroacetyl, tert—butoxycarbonyl (BOC),
benzyloxycarbonyl and 9-fluorenylmethylenoxycarbonyl (Fmoc). For a general description
of protecting groups and their use, see T. W. , Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 1991.
The terms "compound of this invention" and "compounds of the present invention" and
"compounds of formula (l)” include stereoisomers, geometric isomers, tautomers,
solvates, ceutically acceptable salts, and solvates of the salts thereof.
The term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs,
s, dogs, cats, horses, cows, pigs, and sheep. The term "mammal", as used herein,
ably refers to humans.
The t invention provides new difluoromethyl—aminopyridyl- and difluoromethyl-
aminopyrimidinyl-substituted triazines and dines, and pharmaceutical formulations
thereof, which are useful as therapeutic agents and novel diagnostic probes. Moreover,
these compounds are potentially useful in the treatment of diseases, conditions and/or
disorders modulated by protein kinases and lipid kinases.
More specifically, in a first aspect, the present invention provides a compound of formula
(I),
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the o that at least two
of X1, X2 and X3 are N;
Y is N or CH;
R1 and R2 are ndently of each other
(i) a linyl of formula (ll)
Rsi 1R4
f (H)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, ON, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue—
R5R6— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in a (II);
(ii) phenyl optionally substituted with 1 to 3 R7, wherein R7 is independently at each
occurrence halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH,
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3)2;
(iii) a 5- to 6-membered heteroaryl ring W containing one to four heteroatoms
independently ed from N, O and S, optionally substituted by 1 to 3 R8,
wherein R8 is independently at each occurrence halogen, -OH, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl, ycloalkyl, -NH2, NHCH3 or N(CH3)2;
(W) a saturated 4- to 6-membered heterocyclic ring Z ning 1 to 3 heteroatoms
ndently selected from N, O and S, optionally substituted by 1 to 3 R9;
wherein R9 is independently at each occurrence halogen, -OH, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl, Cs-Cscycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9
tuents form together a bivalent residue —R10R11— selected from C1-
Cgalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CHZCH2-O-;
(V) OR”, wherein R12 is C1-Cgalkyl, C1-Cshaloalkyl, C1-Csalkoxy, Cs-Cscycloalkyl,
C1-CzaIkylenecg-Cscycloalkyl; Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-
P represents a saturated 4- to ered cyclic ring containing 1 to 3
heteroatoms independently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
l optionally substituted with one or two OH, uoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3); Q or C1-
leneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl
ring containing one to four heteroatoms independently selected from N, O and
S, optionally substituted by 1 to 3 R14, wherein R14 is independently at each
occurrence halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH,
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3); or
(Vi) NR15R16; wherein R15 and R16 are independently of each other H, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl; Cycle-P or lkyleneCycle-P, wherein Cycle-P
represents a saturated 4- to 6-membered cyclic ring containing 1 to 3
heteroatoms independently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
C3alkyl ally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy,
C1-C2alkoxyC1-C3alkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered aryl
ring containing one to four heteroatoms independently ed from N, O and
S, optionally substituted by 1 to 3 R14, wherein R14 is independently at each
occurrence halogen, -OH, C1-C3alkyl ally tuted with one or two OH,
C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl, -NH2,
NHCH3 or N(CH3);
with the proviso that at least one of R1 and R2 is a morpholinyl of formula II;
and prodrugs, metabolites, tautomers, solvates and pharmaceutically able salts
thereof.
In another , the present invention provides for a compound of formula (I),
xfégfijxg Fm“ WF
95 ’§/~ L
R x3 “rf,» w
i? Y
"M, at‘N
N" am
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N;
Y is N or CH;
R1 and R2 are independently of each other
(i) a morpholinyl of formula (ll)
Rsi 1R4
f (H)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, CN, or C1-C2alkyl; or R3 and R4 form together a bivalent residue—
R5R6— selected from C1-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
n the arrows denote the bonds in formula (II);
(ii) phenyl optionally substituted with 1 to 3 R7, wherein R7 is independently at each
occurrence halogen, -OH, lkyl optionally substituted with one or two OH,
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3)2;
(iii) a 5- to 6-membered heteroaryl ring W ning one to four atoms
independently ed from N, O and S, optionally substituted by 1 to 3 R8,
wherein R8 is independently at each occurrence halogen, -OH, lkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3)2;
(iv) a saturated 4- to 6-membered heterocyclic ring Z containing 1 to 3 heteroatoms
independently selected from N, O and S, optionally tuted by 1 to 3 R9;
wherein R9 is independently at each occurrence halogen, -OH, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl, Cs-Cscycloalkyl, =O, -NH2, NHCH3 or 2; or two R9
substituents form together a bivalent residue 1— selected from C1-
Cgalkylene ally substituted with 1 to 4 F, -CH2- or CH2-O-;
(v) OR”, wherein R12 is C1-Cgalkyl, C1-Cshaloalkyl, C1-Csalkoxy, Cs-Cscycloalkyl,
C1-Czalkylenecg-Cscycloalkyl; Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-
P represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3
heteroatoms independently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
Cgalkyl optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl
ring containing one to four heteroatoms independently selected from N, O and
S, optionally substituted by 1 to 3 R14, wherein R14 is independently at each
occurrence halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH,
C1-szluoroalkyl, lkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3); or
(vi) NR15R16; wherein R15 and R16 are ndently of each other H, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-C3alkyl; Cycle-P or C1-C2alkyleneCycle-P, wherein Cycle-P
represents a saturated 4- to ered heterocyclic ring containing 1 to 3
heteroatoms independently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
C3alkyl optionally substituted with one or two OH, luoroalkyl, C1-C2alkoxy,
C1-C2alkoxyC1-C3alkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
C2alkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl
ring containing one to four heteroatoms ndently selected from N, O and
S, optionally substituted by 1 to 3 R14, wherein R14 is independently at each
occurrence n, -OH, C1-C3alkyl ally substituted with one or two OH,
C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl, -NH2,
NHCH3 or N(CH3);
with the proviso that at least one of R1 and R2 is a morpholinyl of formula II;
and gs, metabolites, tautomers, solvates and pharmaceutically acceptable salts
thereof, and further
with the provisos that
(a) when R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 3-aza
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, 2-methylmorpholinyl,
ylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]octyl, 3-azaoxabicyclo[3.2.1]octy|, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl, 3-aza
oxabicyclo[3.2.1]octyl, razinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
holinyl, octadeuterio—4-morpholinyl, 3-oxabicyclo[3.2.1]octyl or
3-azaoxabicyclo[3.2.1]octy|.
In another aspect, the present invention provides for a compound of formula (I),
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N;
Y is N or CH;
R1 and R2 are independently of each other
(vii)a morpholinyl of formula (ll)
R3: 2 R4
i (ll)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl optionally
substituted with one or two OH, uoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-
Csalkyl, ON, or C(O)O-C1-Czalkyl; or R3 and R4 form er a nt residue —
R5R6— selected from C1-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
H-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II);
(viii)phenyl optionally substituted with 1 to 3 R7, wherein R7 is independently at each
occurrence halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH,
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3)2;
(ix) a 5- to 6-membered heteroaryl ring W containing one to four heteroatoms
independently selected from N, O and S, optionally tuted by 1 to 3 R8,
wherein R8 is ndently at each occurrence n, -OH, C1-Cgalkyl
optionally tuted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3)2;
(x) a saturated 4- to 6-membered heterocyclic ring Z containing 1 to 3 heteroatoms
independently selected from N, O and S, optionally substituted by 1 to 3 R9;
wherein R9 is independently at each occurrence halogen, -OH, lkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl, ycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9
substituents form together a bivalent residue —R10R11— selected from C1-
Cgalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CHZCH2-O-;
(xi) OR”, wherein R12 is C1-Cgalkyl, C1-Cshaloalkyl, C1-Csalkoxy, Cs-Cscycloalkyl,
C1-Czalkylenecg-Cscycloalkyl; Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-
P represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3
heteroatoms independently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
Cgalkyl optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or ; Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl
ring containing one to four heteroatoms independently selected from N, O and
S, optionally substituted by 1 to 3 R14, wherein R14 is ndently at each
occurrence halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH,
C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3); or
(xii) NR15R16; wherein R15 and R16 are independently of each other H, C1-Cgalkyl
optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Cgalkyl; Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-P
represents a saturated 4- to 6-membered cyclic ring containing 1 to 3
heteroatoms independently selected from N, O and S, optionally substituted by
1 to 3 R13, wherein R13 is independently at each occurrence halogen, -OH, C1-
Cgalkyl optionally substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, Cg-Cecycloalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Q represents 5- to 6-membered heteroaryl
ring containing one to four atoms independently selected from N, O and
S, optionally substituted by 1 to 3 R14, wherein R14 is independently at each
occurrence halogen, -OH, C1-Cgalkyl optionally tuted with one or two OH,
C1-szluoroalkyl, lkoxy, lkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2,
NHCH3 or N(CH3);
with the proviso that at least one of R1 and R2 is a morpholinyl of formula II;
and prodrugs, lites, tautomers, solvates and pharmaceutically able salts
thereof, and further
with the proviso that R1 is not holinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 3-oxabicyclo[3.2.1]octyl or 3-
azaoxabicyclo[3.2.1]octyl; and R2 is not 4-morpholinyl, 2-methyl
morpholinyl, ylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]octyl, 3-azaoxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl.
In another aspect, the invention provides for a nd of formula (I),
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH;
R1 is 4-morpholinyl, 2-methylmorpholinyl, ylmorpholinyl, octadeuterio—4-
morpholinyl, 8-azaoxabicyclo[3.2.1]octyl or 3-aza-8—oxabicyclo[3.2.1]octyl; and
R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl, octadeuterio—4-
morpholinyl, 8-azaoxabicyclo[3.2.1]octyl, 3-aza-8—oxabicyclo[3.2.1]octyl,
zinyl, 4-methylpiperazinyl, or 4-thiomorpholinyl.
ln again another aspect, the present invention provides for a compound of formula (I) as
defined herein for use in a method of preventing or treating a disease or disorder
modulated by any one of Pl3Ks, mTOR and PlKKs either individually or in any
combination, n said method ses administering to a mammal in need of such
prevention or treatment an effective amount of said a compound of formula (I). Preferably,
said e or disorder is a hyperproliferative disorder.
In again a r aspect, the present invention provides for a use of a nd of
formula (I) as defined herein in the preparation of a medicament for the ent or
prevention of a disease or condition modulated by any one of Pl3Ks, mTOR and PlKKs
either individually or in any combination, in a mammal, preferably in a human. Preferably,
said disease or disorder is a hyperproliferative disorder.
In again a further aspect, the present invention provides for a use of a compound of
a (I) as defined herein in the manufacture of a medicament for the treatment or
prevention of a disease or condition modulated any one of Pl3Ks, mTOR and PlKKs either
individually or in any combination, in a mammal, preferably in a human. Preferably, said
disease or disorder is a hyperproliferative disorder.
WO 75130
In again another aspect, the present invention provides for a method of preventing or
treating a disease or disorder modulated any one of Pl3Ks, mTOR and PlKKs either
individually or in any combination, wherein said method comprises administering to a
mammal in need of such prevention or ent an effective amount of a compound of
formula (I) as defined .
Each alkyl moiety either alone or as part of a larger group such as alkoxy is a straight or
ed chain and is preferably C1-Cgalkyl, more preferably C1-Czalkyl. Examples
include in particular methyl, ethyl, n-propyl and propyl ropyl). Examples of an
alkoxy include in particular methoxy, ethoxy, n-propoxy and iso-propoxy. As described
herein, alkoxy may include further substitutents such as halogen atoms leading to
haloalkoxy moieties.
The term “alkoxyalkyl” refers to a R-O-R’ moiety in which the R and R’ groups are alkyl
groups as defined herein. Examples include methoxymethyl, methoxyethyl, ethoxyethyl
and methoxypropyl.
Each alkylene moiety is a straight or branched chain and is, particularly for example, -
CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CHZCH3)-,
preferably -CH2-, -CH2-CH2- or -CH(CH3)-.
Each haloalkyl moiety either alone or as part of a larger group such as haloalkoxy is an
alkyl group substituted by one or more of the same or different halogen atoms. Haloalkyl
es include for example 1 to 5 halo tuents, or 1 to 3 halo substituents.
Examples include in particular fluoromethyl, romethyl, trifluoromethyl,
chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.
Each haloalkenyl moiety either alone or as part of a larger group such as haloalkenyloxy
is an alkenyl group substituted by one or more of the same or different halogen atoms.
Examples include,2-difluoro-vinyl and 1,2-dichlorofluoro-vinyl. kenyl moieties
include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.
Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically and preferably in mono-
cyclic form, and preferably contains 3 to 6 carbon atoms. red es of
monocyclic cycloalkyl groups include in particular cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
Halogen is fluorine, ne, bromine, or iodine, preferably fluorine.
The term "heteroaryl" refers to an aromatic ring system containing at least one
heteroatom, and preferably up to four heteroatoms selected from nitrogen, oxygen and
sulfur as ring members. aryl rings do not contain adjacent oxygen atoms, adjacent
sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred examples
include in particular pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, yl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, furanyl, and
thiophenyl
The term "heterocyclic ring" refers to a ted or partially unsaturated carbocyclic ring
containing one to three heteroatoms selected from nitrogen, oxygen and sulfur as ring
members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or
adjacent oxygen and sulfur atoms within the ring. Preferred examples include in particular
tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, olidinyl, piperidinyl, piperazinyl,
dioxanyl, morpholinyl, oxazolidinyl and isooxazolidinyl.
Where a group is said to be ally tuted, preferably there are ally 1-3
substituents, more preferably optionally 1-2 substituents.
n compounds of formula (I) may contain one or two or more centers of chirality and
such compounds may be provided as pure enantiomers or pure diastereoisomers as well
as mixtures thereof in any ratio. The compounds of the invention also include all
tautomeric forms of the compounds of formula (I).
In a red embodiment, the present invention provides for the compound of formula (I)
as defined herein and tautomers, solvates and pharmaceutically acceptable salts thereof.
In r preferred embodiment, the present invention provides for the compound of
formula (I), wherein X1, X2 and X3 are N.
In another preferred embodiment, (i) said x1 and said x2 are N, and said x3 is CH; (ii) said
x1 and said x3 are N, and said x2 is CH; or (iii) said x2 and said x3 are N, and said x1 is
CH, and ably tautomers, solvates and pharmaceutically acceptable salts thereof. In
another embodiment, (i) said X1 and said X2 are N, and said X3 is CH; or (ii) said X2 and
said X3 are N, and said X1 is CH, and ably tautomers, solvates and pharmaceutically
acceptable salts thereof. In another preferred embodiment, said X1 and said X3 are N, and
said X2 is CH; and preferably tautomers, solvates and pharmaceutically acceptable salts
In another preferred embodiment, said Y is N, and preferably tautomers, solvates and
pharmaceutically acceptable salts thereof. In another preferred embodiment, said Y is CH,
and preferably tautomers, solvates and pharmaceutically acceptable salts thereof.
In another preferred embodiment, said R1 and said R2 are independently of each other (i)
a morpholinyl of formula (II); (ii) said 5- to 6-membered aryl ring W; (iii) said
saturated 4- to 6-membered heterocyclic ring 2; (iv) said OR”; or (v) said NR15R16.
In another preferred embodiment, said R1 and said R2 are independently of each other
ed from
[E1 [EL [EL [EL ,EEL ,erlr
“15.th ESL, EELE [Ef- TE‘J’ TEL
lr l l i ii lg
[ELL [ELLEEJ’[ET[EEJQ
m m [EL Cl
{E}: EED [E1:
[3" Ci
E? Q [j El “Q
E13 $53963?wa
i i i i + i i
”i" ‘i‘ Pi i" F
L9 Lmé L w
1* ii ilr lr i ii
WO 75130
m f—‘a. /_/<
[:>—N fierH—HMa" Q N —1-~
3—? 3—.” 3—." 3—,!
., N
N “I‘M__ H H
In another preferred ment, said R1 and said R2 are independently of each other
selected from
Q {[21 x: $313
EELKEEf'YEfTEL ["tj‘H
CRQ$ 88w
$3: E:3: [5:3: $3 $3 $31Ir
:3» F’ F
N N
+ + + 5?
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[EL/F [$ij (Elf:
D E
[:>—N N+ xix: Ha- 1:3 ran.
F F F F
“‘ "““
'3‘“ ‘~ | “H
":3 N—h— I
f f I
" ‘~_f HEN N HEN N N
ff; Hi H
“a EMa
[NJ-"’7"
Q N; NJ
I 0
r r' A '3 L
N N DH H D H
F-d"
i _| N ll
| .H IHH L: M l
m' ”*N H H N‘N NEE",
F H F H
F . F l
. |
F>'\/r~41 F, Mi Mi mama
'7' F F D
F D‘s-t
In another preferred embodiment, R1 and R2 are independently of each other selected
from
N [Elm 61(3)” if g;
l E l l +‘
$ 3 Na. HN isle-r —M Ma-
i._f i._.i 3—3“
In another preferred embodiment, R1 and R2 are ndently of each other selected
from
£23 ESL [fl E53 [01¢ ijk
i l l l l l
,rjj..,,,, Erik *w W
1Ir 1
In another preferred ment, said nd of formula (I) is selected from
4-(difluoromethyl)—5-(4,6-dimorpholino—1,3,5-triazinyl)pyridinamine;
4-(difluoromethyl)—5-(4,6-dimorpholino—1,3,5-triazinyl)pyrimidinamine;
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)(3-oxa-8—azabicyclo[3.2.1]octan-8—y|)—1 ,3,5-
triazinyl)—4-(difluoromethyl)pyridinamine;
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)—6-morpholino—1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyridinamine;
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)—6-morpholino—1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyrimidinamine;
-(4,6-bis((S)—3-methy|morpholino)—1,3,5-triaziny|)(difluoromethyl)pyridinamine;
-(4,6-bis((S)—3-methy|morpholino)—1,3,5-triaziny|)(difluoromethyl)pyrimidinamine;
(S)—4-(difluoromethyl)(4-(3-methy|morpho|ino)—6-morpholino—1,3,5-triaziny|)pyridin
amine;
(difluoromethyl)(4-(3-methy|morpho|ino)—6-morpholino—1,3,5-triaziny|)pyrimidin-
2-amine;
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)((S)—3-methy|morpho|ino)—1,3,5-triazinyl)—4-
(difluoromethyl)pyridinamine;
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)((S)—3-methy|morpho|ino)—1,3,5-triazinyl)—4-
(difluoromethyl)pyrimidinamine;
4-(difluoromethyl)(4-morpho|ino—6-(piperaziny|)-1,3,5-triazinyl)pyridinamine;
4-(difluoromethyl)(4-morpho|ino—6-(piperaziny|)-1,3,5-triazinyl)pyrimidinamine;
(S)—4-(difluoromethyl)(4-(3-methy|morpho|ino)—6-(piperaziny|)-1,3,5-triazin
y|)pyridinamine;
(S)—4-(difluoromethyl)(4-(3-methy|morpho|ino)—6-(piperaziny|)-1,3,5-triazin
y|)pyrimidinamine;
4-(difluoromethyl)—5-(2,6-dimorpholinopyrimidiny|)pyridinamine;
4'-(difluoromethyl)—2,6-dimorpholino—[4,5'-bipyrimidin]—2'-amine;
4-(difluoromethyl)—5-(4,6-dimorpholinopyrimidiny|)pyridinamine;
4'-(difluoromethyl)—4,6-dimorpholino—[2,5'-bipyrimidin]—2'-amine;
4-(difluoromethyl)(4-morpho|ino—6-thiomorpholino—1,3,5-triaziny|)pyridinamine;
4-(difluoromethyl)(4-morpho|ino—6-thiomorpholino—1,3,5-triaziny|)pyrimidinamine;
-(6-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octan-8—
y|)pyrimidiny|)(difluoromethyl)pyridinamine;
3-oxaazabicyclo[3.2.1]octany|)morpho|inopyrimidiny|)
(difluoromethyl)pyridinamine;
2-(3-oxaazabicyclo[3.2.1]octan-8—y|)—4’-(difluoromethyl)—6-morpholino—[4,5’-bipyrimidin]—
2’-amine;
-(2,6-bis((S)—3-methy|morpholino)pyrimidiny|)(difluoromethyl)pyridinamine;
4'-(difluoromethyl)-2,6-bis((S)—3-methy|morpholino)—[4,5'-bipyrimidin]—2'-amine;
(difluoromethyl)(6-(3-methy|morpho|ino)—2-morpholinopyrimidinyl)pyridin
amine;
(S)—4'-(difluoromethyl)(3-methy|morpholino)—2-morpholino—[4,5'-bipyrimidin]—2'-amine;
-(4-(8—Oxaazabicyclo[3.2.1]octany|)(8—oxaazabicyclo[3.2.1]octany|)—1 ,3,5-
triazinyl)—4-(difluoromethyl)pyridinamine;
5-[4,6-bis(2,2-dimethylmorpholinyl)—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
(S)—4-(difluoromethyl)(2-(3-methy|morpholino)—6-morpholinopyrimidinyl)pyridin
amine;
-(difluoromethyl)(3-methy|morpholino)—6-morpholino—[4,5'-bipyrimidin]—2'-amine;
4-(difluoromethyl)—5-[4-[(28,6R)—2,6-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
-[4,6-bis[(2R,6S)—2,6-dimethylmorpholiny|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridin-
2-amine;
4-[4-[6-amino—4-(difluoromethyl)pyridy|]—6-morpho|ino—1,3,5-triazinyl]morpholin
one;
4-[4-[2-amino—4-(difluoromethyl)pyrimidinyl]—6-morpholino—1,3,5-triazinyl]morpholin
one;
-[4,6-bi3(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—6-(3-oxa-8—
azabicyclo[3.2.1]octan-8—y|)—1,3,5-triazinyl]pyridinamine;
-[4,6-bis(3,3-dimethylmorpholinyl)—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
-[4,6-bis[(3R,58)—3,5-dimethylmorpholiny|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridin-
2-amine;
-[4,6-bis[(3R)—3-methy|morpholinyl]—1,3,5-triazinyl]—4-(difluoromethyl)pyridin
amlne;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-morpholino—1,3,5-triaziny|]pyridin-
2-amine;
-[4-[6-amino—4-(difluoromethyl)pyridy|]—6-[(3R)—3-methy|morpholinyl]—1,3,5-triazin
y|](difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R)—3-methy|morpholinyl]—1 ,3,5-
triazinyl]pyridinamine;
luoromethyl)[4-[(3R)—3-(methoxymethyl)morpholinyl]—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)[4-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triaziny|]pyridinamine;
(4S,5R)—3-[4-[2-amino—4-(difluoromethyl)pyrimidinyl]—6-morpholino—1,3,5-triazinyl]—4-
(hydroxymethyl)—5-methy|—oxazolidinone;
(4S,5R)—3-[6-[2-amino—4-(difluoromethyl)pyrimidinyl]—2-morpholino—pyrimidiny|]
(hydroxymethyl)—5-methy|—oxazolidinone;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](3-oxaazabicyclo[3.1.1]heptan-
6-y|)-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](6-oxaazabicyclo[3.1.1]heptan-
3-y|)-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(1R,4R)—2-oxa
azabicyc|o[2.2.1]heptany|]—1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(1S,4S)—2-oxa
azabicyc|o[2.2.1]heptany|]—1,3,5-triazinyl]pyridinamine;
-[4,6-bis[(3R)—3-ethy|morpholinyl]—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
5-[4,6-bis(8—oxaazaspiro[3.5]nonanyI)-1,3,5-triazinyl]—4-(difluoromethyl)pyridin-2—
amine;
-[4,6-bis[(3R)—3-isopropy|morpholinyl]—1,3,5-triaziny|](difluoromethyl)pyridin
amine;
4-[6-amino—4-(difIuoromethyl)pyridy|]-N-methy|—6-[(3R)—3-methy|morpholinyl]—Ntrifluoroethyl)—1,3,5-triazinamine;
4-[6-amino—4-(difIuoromethyl)pyridy|][(3R)—3-methy|morpholinyl]—N-(2,2,2-
oroethyl)—1,3,5-triazinamine;
4-[6-amino—4-(difIuoromethyl)pyridy|]-N-(cyc|opropy|methyl)[(3R)—3-methy|morpholin-
4-y|]-1,3,5-triazinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2,2,2-trifluoroethoxy)—1,3,5-triazin-
2-yl]pyridinamine;
-[4-(2,2-difluoroethoxy)—6-[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine;
-[4-[(3aR,6aS)—1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrro|y|][(3R)—3-methy|morpholin-
4-y|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
-[4-[(4aS,7aR)—2,3,4a,5,7,7a-hexahydro—[1,4]dioxino[2,3-0]pyrrolyl]—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triaziny|](difluoromethyl)pyridinamine;
4-(difluoromethyl)—5-[4-(4,4-difluoro—1-piperidyl)[(3R)—3-methy|morpholinyl]—1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2-oxaazaspiro[3.5]nonany|)—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R,58)—3,5-dimethylmorpholin
y|]-1,3,5-triaziny|]pyridinamine;
luoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R)—3-(methoxymethyl)morpholin-
4-y|]-1,3,5-triazinyl]pyridinamine;
[(3R)—4-[4-[6-amino—4-(difluoromethyl)pyridy|]—6-(3,3-dimethylmorpholinyl)—1 ,3,5-
triazinyl]morpholinyl]methanol;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-(3,7-dioxa-9—
yclo[3.3.1]nonan-9—y|)—1,3,5-triazinyl]pyridinamine;
4-cyclopropylpiperaziny|)(3,3-dimethylmorpholinyl)—1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[4-(2-methoxyethyl)piperaziny|]-
triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)(oxetany|oxy)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-[(3S)—tetrahyd rofurany|]oxy-1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-[(3R)—tetrahyd rofurany|]oxy-1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-tetrahydropyranyloxy-1,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-(1,1-dioxo—1,4-thiazinany|)-1,3,5-
triazinyl]pyridinamine;
[(3R)—4-[4-[6-amino—4-(difluoromethyl)pyridyl]—6-[(3R)—3-methy|morpholinyl]—1 ,3,5-
triazinyl]morpholinyl]methanol;
4-(difluoromethyl)[4-[(3R,5R)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)[4-[(3S,58)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)—5-[4-morpholino—6-(3-oxa-9—azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazin
y|]pyridinamine;
-[4,6-bis(3-oxa-9—azabicyc|o[3.3.1]nonan-9—yI)-1,3,5-triazin-2—yl]—4-(difluoromethyl)pyridin-
2-amine;
-[4-[6-amino—4-(difluoromethyl)pyridy|]—6-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—
1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
luoromethyl)[4-[(3R)—3-methy|morpholiny|](4-morpho|ino—1-piperidy|)—1 ,3,5-
triazinyl]pyridinamine;
-[4-(4-cyclopropylpiperaziny|)[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine;
-[4-(4-Cyclopropylpiperaziny|)[(3S,5R)—3,5-dimethylmorpholinyl]—1,3,5-triazin
y|](difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-[4-(2-methoxyethyl)piperaziny|][(3R)—3-methy|morpholinyl]—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-[4-(2-
methoxyethyl)piperaziny|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-(4-morpho|ino—1-piperidy|)—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(1,1-dioxo—1,4-thiazinanyl)[(3R)—3-methy|morpholinyl]—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-(1,1-dioxo—1,4-thiazinan
y|)-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|]tetrahydropyranyloxy-1,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-tetrahyd ropyranyloxy-
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(3S)—tetrahydrofurany|]oxy-
triazinyl]pyridinamine;
luoromethyl)[4-[(3R)—3-methy|morpholinyl][(3R)—tetrahyd rofurany|]oxy-
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholiny|][(3S)—tetrahydrofuran
-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-[(3R)—tetrahyd rofuran
y|]oxy-1,3,5-triazinyl]pyridinamine;
2015/076192
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](oxetanyloxy)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholiny|](oxetanyloxy)—1,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-(3,7-dioxa-9—
azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazinyl]pyridinamine;
3-[4-[6-amino—4-(difluoromethyl)pyridyl]—6-[(3R,58)—3,5-dimethylmorpholinyl]—1 ,3,5-
ny|]oxazo|idinone;
-(4-((1R,2R,48,5S)—7-oxa-9—azatricyclo[3.3.1.02‘4]nonan-9—yl)((2R,4S)—7-oxa-9—
cyclo[3.3.1.02‘4]nonanyI)-1,3,5-triazinyl)—4-(difluoromethyl)pyridinamine;
-[4,6-bis(6,6-difluoro—3-oxa-8—azabicyclo[3.2.1]octan-8—yI)-1,3,5-triazinyI]
(difluoromethyl)pyridinamine;
-[4,6-bis(6,7-difluoro—3-oxa-8—azabicyclo[3.2.1]octan-8—yI)-1,3,5-triazinyI]
(difluoromethyl)pyridinamine;
5-[4-(6-amino—3-pyridyl)[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine;
4-(difluoromethyl)—5-[4-[4-(difluoromethyl)pyridy|]—6-[(3R)—3-methy|morpholinyl]—1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morph0|iny|](3-pyridy|)-1,3,5-triazinyl]pyridin-
2-amine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|]pyraziny|-1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-pyrazolyl)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-pyrazolyl)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1,2,4-triazoly|)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-1,2,4-triazoly|)—1,3,5-triazin-
2-yl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2H-tetrazolyl)—1,3,5-triazin
y|]pyridinamine.
In another red embodiment, said compound of formula (I) is selected from
4-(difluoromethyl)—5-(4,6-dimorpholino—1,3,5-triazinyl)pyridinamine;
4-(difluoromethyl)—5-(4,6-dimorpholino—1,3,5-triazinyl)pyrimidinamine;
-(4-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octan-8—y|)—1 ,3,5-
nyl)—4-(difluoromethyl)pyridinamine;
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)—6-morpholino—1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyridinamine;
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)—6-morpholino—1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyrimidinamine;
-(4,6-bis((S)—3-methy|morpholino)—1,3,5-triazinyl)—4-(difluoromethyl)pyridinamine;
-(4,6-bis((S)—3-methy|morpholino)—1,3,5-triazinyl)—4-(difluoromethyl)pyrimidinamine;
(S)—4-(difluoromethyl)(4-(3-methy|morpho|ino)—6-morpholino—1,3,5-triaziny|)pyridin
amine;
(difluoromethyl)(4-(3-methy|morpho|ino)—6-morpholino—1,3,5-triaziny|)pyrimidin-
2-amine;
-(4-(3-oxaazabicyc|o[3.2.1]octan-8—y|)((S)—3-methy|morpho|ino)—1,3,5-triazinyl)—4-
(difluoromethyl)pyridinamine;
5-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)((S)—3-methy|morpho|ino)—1,3,5-triazinyl)—4-
(difluoromethyl)pyrimidinamine;
4-(difluoromethyl)(4-morpholino—6-(piperaziny|)-1,3,5-triazinyl)pyridinamine;
4-(difluoromethyl)(4-morpho|ino—6-(piperaziny|)-1,3,5-triazinyl)pyrimidinamine;
(S)—4-(difluoromethyl)(4-(3-methy|morpho|ino)—6-(piperaziny|)-1,3,5-triazin
y|)pyridinamine;
(S)—4-(difluoromethyl)(4-(3-methy|morpho|ino)—6-(piperaziny|)-1,3,5-triazin
y|)pyrimidinamine;
4-(difluoromethyl)—5-(2,6-dimorpholinopyrimidiny|)pyridinamine;
4'-(difluoromethyl)—2,6-dimorpholino—[4,5'-bipyrimidin]—2'-amine;
4-(difluoromethyl)—5-(4,6-dimorpholinopyrimidiny|)pyridinamine;
4'-(difluoromethyl)—4,6-dimorpholino—[2,5'-bipyrimidin]—2'-amine;
4-(difluoromethyl)(4-morpho|ino—6-thiomorpholino—1,3,5-triaziny|)pyridinamine;
4-(difluoromethyl)(4-morpho|ino—6-thiomorpholino—1,3,5-triaziny|)pyrimidinamine;
-(6-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octan-8—
y|)pyrimidiny|)(difluoromethyl)pyridinamine;
-(2—(3-oxaazabicyclo[3.2.1]octany|)morpho|inopyrimidiny|)
oromethyl)pyridinamine;
2-(3-oxaazabicyclo[3.2.1]octan-8—y|)—4’-(difluoromethyl)—6-morpholino—[4,5’-bipyrimidin]—
2’-amine;
5-(2,6-bis((S)—3-methy|morpholino)pyrimidiny|)(difluoromethyl)pyridinamine;
4'-(difluoromethyl)-2,6-bis((S)—3-methy|morpholino)—[4,5'-bipyrimidin]—2'-amine;
WO 75130
(S)—4-(difluoromethyl)(6-(3-methy|morpho|ino)morpho|inopyrimidiny|)pyridin
amine;
(S)—4'-(difluoromethyl)(3-methy|morpho|ino)—2-morpho|ino-[4,5'-bipyrimidin]-2'-amine;
-(4-(8—Oxaazabicyclo[3.2.1]octanyl)(8—oxaazabicyclo[3.2.1]octany|)—1 ,3,5-
triaziny|)(difluoromethyl)pyridinamine;
-[4,6-bis(2,2-dimethylmorpholinyl)—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
(S)—4-(difluoromethyl)(2-(3-methy|morpho|ino)morpho|inopyrimidiny|)pyridin
amine;
(S)—4'-(difluoromethyl)(3-methy|morpholino)—6-morpho|ino-[4,5'-bipyrimidin]-2'-amine;
4-(difluoromethyl)—5-[4-[(28,6R)—2,6-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
-[4,6-bis[(2R,6S)—2,6-dimethylmorpholiny|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridin-
2-amine.
In another preferred ment, said compound of formula (I) is ed from
4-[4-[6-amino(difluoromethyl)pyridy|]—6-morpho|ino-1,3,5-triaziny|]morpho|in
one;
4-[4-[2-amino(difluoromethyl)pyrimidinyl]—6-morpholino-1,3,5-triaziny|]morpho|in
one;
5-[4,6-bi3(3,7-dioxa-9—azabicyc|o[3.3.1]nonany|)—1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-(3,7-dioxa-9—azabicyc|o[3.3.1]nonan-9—y|)—6-(3-oxa-8—
azabicyclo[3.2.1]octan-8—y|)—1,3,5-triazinyl]pyridinamine;
-[4,6-bis(3,3-dimethylmorpholinyl)—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
5-[4,6-bis[(3R,58)—3,5-dimethylmorpholiny|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridin-
2-amine;
-[4,6-bis[(3R)—3-methy|morpholiny|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridin
amine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-morpholino-1,3,5-triaziny|]pyridin-
2-amine;
-[4-[6-amino(difluoromethyl)pyridy|]—6-[(3R)—3-methy|morpholiny|]-1,3,5-triazin
y|](difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R)—3-methy|morpholiny|]-1,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-(methoxymethyl)morpholinyl]—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)[4-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—6-[(3R)—3-
morpholinyl]—1,3,5-triaziny|]pyridinamine;
(4S,5R)—3-[4-[2-amino—4-(difluoromethyl)pyrimidinyl]—6-morpholino—1,3,5-triazinyl]—4-
(hydroxymethyl)—5-methy|—oxazolidinone;
(4S,5R)—3-[6-[2-amino—4-(difluoromethyl)pyrimidinyl]—2-morpholino—pyrimidiny|]
(hydroxymethyl)—5-methy|—oxazolidinone;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](3-oxaazabicyclo[3.1.1]heptan-
6-y|)-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](6-oxaazabicyclo[3.1.1]heptan-
3-y|)-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(1R,4R)—2-oxa
azabicyc|o[2.2.1]heptany|]—1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(1S,4S)—2-oxa
azabicyc|o[2.2.1]heptany|]—1,3,5-triazinyl]pyridinamine;
-[4,6-bis[(3R)—3-ethy|morpholinyl]—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
-[4,6-bis(8—oxaazaspiro[3.5]nonanyI)-1,3,5-triazinyl]—4-(difluoromethyl)pyridin-2—
amine;
5-[4,6-bis[(3R)—3-isopropy|morpholinyl]—1,3,5-triaziny|](difluoromethyl)pyridin
amine;
4-[6-amino—4-(difIuoromethyl)pyridy|]-N-methy|—6-[(3R)—3-methy|morpholinyl]—N-
(2,2,2-trifluoroethyl)—1,3,5-triazinamine;
4-[6-amino—4-(difIuoromethyl)pyridy|][(3R)—3-methy|morpholinyl]—N-(2,2,2-
trifluoroethyl)—1,3,5-triazinamine;
4-[6-amino—4-(difIuoromethyl)pyridy|]-N-(cyc|opropy|methyl)[(3R)—3-methy|morpholin-
4-y|]-1,3,5-triazinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2,2,2-trifluoroethoxy)—1,3,5-triazin-
2-yl]pyridinamine;
5-[4-(2,2-difluoroethoxy)—6-[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine;
-[4-[(3aR,6aS)—1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrro|y|][(3R)—3-methy|morpholin-
4-y|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
-[4-[(4aS,7aR)—2,3,4a,5,7,7a-hexahydro—[1,4]dioxino[2,3-0]pyrrolyl]—6-[(3R)—3-
morpholinyl]—1,3,5-triaziny|](difluoromethyl)pyridinamine;
4-(difluoromethyl)—5-[4-(4,4-difluoro—1-piperidyl)[(3R)—3-methy|morpholinyl]—1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2-oxaazaspiro[3.5]nonany|)—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R,58)—3,5-dimethylmorpholin
y|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R)—3-(methoxymethy|)morpholin-
1,3,5-triazinyl]pyridinamine;
[(3R)—4-[4-[6-amino—4-(difluoromethyl)pyridy|]—6-(3,3-dimethylmorpholinyl)—1 ,3,5-
triazinyl]morpholinyl]methanol;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-(3,7-dioxa-9—
azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazinyl]pyridinamine;
-[4-(4-cyclopropylpiperaziny|)(3,3-dimethylmorpholinyl)—1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[4-(2-methoxyethy|)piperaziny|]-
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)(oxetany|oxy)—1,3,5-triazin
idinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-[(3S)—tetrahyd rofurany|]oxy-1 ,3,5-
nyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-[(3R)—tetrahyd rofurany|]oxy-1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-tetrahydropyranyloxy-1,3,5-
triazinyl]pyridinamine;
luoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-(1,1-dioxo—1,4-thiazinany|)-1,3,5-
triazinyl]pyridinamine;
[(3R)—4-[4-[6-amino—4-(difluoromethyl)pyridyl]—6-[(3R)—3-methy|morpholinyl]—1 ,3,5-
triazinyl]morpholinyl]methanol;
4-(difluoromethyl)[4-[(3R,5R)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)[4-[(3S,58)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)[4-morpho|ino—6-(3-oxa-9—azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazin
y|]pyridinamine;
-[4,6-bis(3-oxa-9—azabicyc|o[3.3.1]nonan-9—yI)-1,3,5-triazin-2—yl]—4-(difluoromethyl)pyridin-
2-amine;
-[4-[6-amino—4-(difluoromethyl)pyridy|]—6-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—
1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](4-morpho|ino—1-piperidy|)—1 ,3,5-
triazinyl]pyridinamine;
-[4-(4-cyclopropylpiperaziny|)[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine;
-[4-(4-Cyclopropylpiperaziny|)[(3S,5R)—3,5-dimethylmorpholinyl]—1,3,5-triazin
y|](difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-[4-(2-methoxyethyl)piperaziny|][(3R)—3-methy|morpholinyl]—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-[4-(2-
methoxyethyl)piperaziny|]-1,3,5-triaziny|]pyridinamine;
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-(4-morpho|ino—1-piperidy|)—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(1,1-dioxo—1,4-thiazinanyl)[(3R)—3-methy|morpholinyl]—
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-(1,1-dioxo—1,4-thiazinan
y|)-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|]tetrahydropyranyloxy-1,3,5-
triazinyl]pyridinamine;
luoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-tetrahyd nyloxy-
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(3S)—tetrahydrofurany|]oxy-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholinyl][(3R)—tetrahyd rofurany|]oxy-
1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholiny|][(3S)—tetrahydrofuran
y|]oxy-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-[(3R)—tetrahyd rofuran
y|]oxy-1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](oxetanyloxy)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-(oxetanyloxy)—1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-(3,7-dioxa-9—
yclo[3.3.1]nonan-9—y|)—1,3,5-triazinyl]pyridinamine;
3-[4-[6-amino—4-(difluoromethyl)pyridyl]—6-[(3R,58)—3,5-dimethylmorpholinyl]—1 ,3,5-
nyl]oxazolidinone;
-(4-((1R,2R,4S,5S)—7-oxa-9—azatricyc|o[3.3.1.02*4]nonany|)((2R,4S)—7-oxa-9—
azatricyclo[3.3.1.02‘4]nonany|)-1,3,5-triazinyl)—4-(difluoromethyl)pyridinamine;
-[4,6-bis(6,6-difluorooxa-8—azabicyclo[3.2.1]octany|)—1,3,5-triazinyI]
(difluoromethyl)pyridinamine;
-[4,6-bis(6,7-difluorooxa-8—azabicyc|o[3.2.1]octany|)—1,3,5-triazinyI]
(difluoromethyl)pyridinamine;
-[4-(6-aminopyridyl)[(3R)—3-methy|morpholiny|]-1,3,5-triaziny|]
(difluoromethyl)pyridinamine;
4-(difluoromethy|)[4-[4-(difluoromethyl)pyridyl]—6-[(3R)—3-methy|morpholiny|]-1,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](3-pyridy|)-1,3,5-triaziny|]pyridin
2-amine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|]pyraziny|—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-pyrazolyl)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-pyrazolyl)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1,2,4-triazo|—1-y|)—1,3,5-triazin
y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-1,2,4-triazo|—3-y|)—1,3,5-triazin-
2-y|]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2H-tetrazoIy|)-1,3,5-triazin
y|]pyridinamine.
In another preferred embodiment, said compound of formula (I) is ed from the group
ting of
- 4-(difluoromethyl)—5-(4,6-dimorpholino-1,3,5-triaziny|)pyrimidinamine;
- 3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octan-8—y|)—1 ,3,5-
triazinyl)—4-(difluoromethyl)pyridinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)—6-morpho|ino-1,3,5-triazin-2—y|)
(difluoromethyl)pyridinamine;
- 5-(4,6-bis((S)methy|morpho|ino)—1,3,5-triaziny|)(difluoromethyl)pyrimidin
amine;
- (S)(difluoromethyl)(4-(3-methylmorpholino)—6-morpholino-1,3,5-triazinyl)pyridin-
2-amine;
- 4-(difluoromethyl)(4-morpholino(piperazinyl)-1,3,5-triazinyl)pyrimidinamine;
- 4-(difluoromethyl)—5-(4,6-dimorpholino-1,3,5-triazinyl)pyridinamine; and
- (S)(difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazin
y|)pyrimidinamine;
and tautomers, solvates and pharmaceutically acceptable salts thereof.
In another preferred embodiment, said nd of formula (I) is selected from
- 4-(difluoromethyl)—5-(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octanyl)-1,3,5-
triazinyl)—4-(difluoromethyl)pyridinamine;
- (S)(difluoromethyl)(4-(3-methylmorpholino)—6-morpholino-1,3,5-triazinyl)pyridin-
2-amine;
and tautomers, solvates and pharmaceutically acceptable salts f.
In another very preferred ment, said compound of formula (I) is 4-(difluoromethyl)-
-(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine.
In another very red embodiment, said compound of formula (I) is 4-(difluoromethyl)-
-(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine; and tautomers, solvates and
ceutically acceptable salts thereof.
In another very preferred ment, said nd of formula (I) is 5-(4-(3-oxa
azabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octanyl)-1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyridinamine.
In another very preferred embodiment, said compound of formula (I) is 5-(4-(3-oxa
azabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octanyl)-1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable
salts thereof.
In another very preferred embodiment, said compound of formula (I) is (S)
(difluoromethyl)(4-(3-methylmorpholino)—6-morpholino-1,3,5-triazinyl)pyridin
amine.
In another very red embodiment, said compound of formula (I) is (S)
(difluoromethyl)(4-(3-methylmorpholino)—6-morpholino-1,3,5-triazinyl)pyridin
amine; and tautomers, solvates and pharmaceutically acceptable salts thereof.
In another preferred embodiment, said compound of formula (I) is selected from
4-[4-[6-amino(difluoromethyl)pyridyl]—6-morpholino-1,3,5-triazinyl]morpholin
one;
4-[4-[2-amino(difluoromethyl)pyrimidinyl]—6-morpholino-1,3,5-triazinyl]morpholin
one;
5-[4,6-bis(3,7-dioxa-9—azabicyclo[3.3.1]nonanyl)—1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—yl)—6-(3-oxa-8—
azabicyclo[3.2.1]octanyl)-1,3,5-triazinyl]pyridinamine;
-[4,6-bis(3,3-dimethylmorpholinyl)—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine;
5-[4,6-bis[(3R,58)—3,5-dimethylmorpholinyl]-1,3,5-triazinyl]—4-(difluoromethyl)pyridin-
2-amine;
-[4,6-bis[(3R)—3-methylmorpholinyl]—1,3,5-triazinyl]—4-(difluoromethyl)pyridin
amine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-morpholino-1,3,5-triazinyl]pyridin-
2-amine;
-[4-[6-amino(difluoromethyl)pyridyl]—6-[(3R)—3-methylmorpholinyl]—1,3,5-triazin
yl]—4-(difluoromethyl)pyridinamine;
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methylmorpholin
yl]—1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R)—3-methylmorpholinyl]—1 ,3,5-
triazinyl]pyridinamine;
4-(difluoromethyl)[4-[(3R)—3-(methoxymethyl)morpholinyl]—6-[(3R)—3-
morpholinyl]—1,3,5-triazinyl]pyridinamine;
4-(difluoromethyl)[4-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—yl)—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triazinyl]pyridinamine;
(4S,5R)—3-[4-[2-amino(difluoromethyl)pyrimidinyl]—6-morpholino-1,3,5-triazinyl]—4-
(hydroxymethyl)methyI-oxazolidinone; and tautomers, es and pharmaceutically
able salts thereof.
In another preferred embodiment, said compound of formula (I) is (4S,5R)—3-[4-[2-amino-
4-(difluoromethyl)pyrimidinyl]—6-morpholino-1,3,5-triazinyl]—4-(hydroxymethyl)—5-
-oxazolidinone.
In another red embodiment, said compound of formula (I) is (4S,5R)—3-[4-[2-amino-
4-(difluoromethyl)pyrimidinyl]—6-morpholino-1,3,5-triazinyl]—4-(hydroxymethyl)—5-
methyl-oxazolidinone; and tautomers, es and pharmaceutically acceptable salts
thereof.
In another preferred ment, said R1 and R2 are independently of each other a
morpholinyl of formula (II). In one preferred embodiment, said R1 is equal to R2. In another
preferred embodiment, said R1 is not equal to R2.
In another preferred embodiment, said R1 and R2 are independently of each other a
morpholinyl of formula (II) and said 5- to 6-membered heteroaryl ring W.
In another preferred embodiment, said R1 and R2 are independently of each other a
morpholinyl of a (II) and said saturated 4- to 6-membered heterocyclic ring Z.
In r preferred embodiment, said R1 and R2 are independently of each other a
morpholinyl of formula (II) and said OR12.
In another preferred embodiment, said R1 and R2 are independently of each other a
morpholinyl of formula (II) and said NR15R16.
In another preferred embodiment, within said morpholinyl of formula (ll)
Rsfi 1R4
I (II)
R3 and R4 are independently of each other H, C1-Cgalkyl optionally substituted with one or
two OH, uoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, ON, or C(O)O-C1-Czalkyl;
or R3 and R4 form together a bivalent residue —R5R6— selected from C1-Cgalkylene
optionally substituted with 1 to 4 F, -CH2-O-CH2-, H-CH2-, or any of the structures
/ \ I \ ; wherein the arrows denote the bonds in formula (II).
In the instance that R3 and R4 together form a nt residue and are bound to vicinal
carbon atoms annulated morpholinyl substituents are formed. In the instance that R3 and
R4 together form a bivalent residue and are spanning across the morpholine ring bridged
morpholinyl substituents are . In the ce that R3 and R4 together form a
bivalent residue and are bound to the same carbon atom of the morpholine, spiro
morpholinyl substituents are formed.
In a preferred embodiment, R3 and R4 form together a bivalent residue —R5R6— selected
from C1-Cgalkylene optionally substituted with 1 to 4 F, -CH2-, -CH2-NH-CH2-, or
any of the structures
f O
and forming a bridged morpholinyl substituent.
In another preferred embodiment, said R1 and R2 are independently of each other a
morpholinyl of formula (II), wherein R3 and R4 form together a bivalent residue leading to a
bridged morpholinyl, wherein R3 and R4 form together a bivalent residue —R5R6— selected
from lkylene, preferably C1-Czalkylene, -CHZCF2-, -CHFCHF-, -CHZCFZCH2-, -CH2-
O-CH2-, -CH2-NH-CH2-, or any of the structures
/ \ I \ ; wherein the arrows denote the bonds in formula (II).
In a further preferred embodiment, said morpholinyl of formula (ll)
Rsi 1R4
i (II)
is independently of each other a morpholinyl of said formula (II), wherein R3 and R4 are
ndently of each other H, C1-Csalkyl, CHZOH, CHZCHZOH, CH2F, CHF2, CF3,
CHZCFs, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, ON, or C1-Czalkyl; or R3 and R4 form
together a bivalent residue —R5R6— selected from C1-Cgalkylene, preferably C1-Czalkylene,
-CH2CF2-, F-, 2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the
stru ctu res
i \ I \ ; wherein the arrows denote the bonds in formula (II).
In a further preferred embodiment, said linyl of formula (II) is independently of
each other a morpholinyl of said formula (II), wherein R3 and R4 are independently of each
other H or CH3.
In a further preferred embodiment, said morpholinyl of formula (II) is independently of
each other a morpholinyl of said formula (II), wherein R3 and R4 are ndently of each
other CZ-Csalkyl, CHZOH, CHZCHZOH, CH2F, CHF2, CF3, CHZCFs, C1-Czalkoxy, C1-
xyC1-Cgalkyl, ON, or C(O)O-C1-Cza|kyl; or R3 and R4 form together a bivalent
residue —R5R6— selected from —CH2— or Cgalkylene, preferably —CH2—, -CHZCF2-, -
CHFCHF-, -CHZCFZCH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures
/ \ I \ ; wherein the arrows denote the bonds in formula (II).
In a further preferred embodiment, said morpholinyl of formula (II) is independently of
each other ed from
[E1 [EL [EL [EL ,EEL ,erl
o [a or r3 1:} a
L MW1%
[ELL [ELLEEJ’[ET[EEJQ
Q Q [EL IZEI
{E}: EE13 [EE0]:
o :3»
@ewee%%, a 3 E} 21:}
* i l l l l i
M L? {$35 M El F
VF wI3 '3" [G ‘3‘
r F‘ F E F
N N NL N jfi/ Njfi< F
i if l if F + F
['3' I Ci 1:»
a E E E
l a.
a + N i +
In a further preferred embodiment, said morpholinyl of formula (II) is independently of
each other selected from
[Ct] [01 [I33 [It [[3, [1
lil E -.--.-__I_ L E E :k
'3 :1 E All: j\
_ [It
In D i |
,r J. E L a w
M N A ll
1i 1i DH 1*
In a further preferred ment, R1 or R2 is said 5- to 6-membered heteroaryl ring W.
WO 75130
In a further preferred embodiment, said one to four atoms of said 5- to 6-membered
heteroaryl ring W are solely N, and n said 6-membered heteroaryl ring W is
optionally substituted by 1 to 3 R8, wherein R8 is independently at each occurrence
halogen, -OH, C1-Cgalkyl optionally substituted with one or two OH, C1-szluoroalkyl, C1-
Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, -NH2, NHCH3 or N(CH3)2; and
tautomers, solvates and pharmaceutically able salts f. Preferably, said 5- to
6-membered heteroaryl ring W containing one to four N is optionally substituted by 1 to 3
R8, wherein R8 is independently at each occurrence halogen, -OH, lkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, , C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-
Cscycloalkyl, -NH2, NHCH3 or N(CH3)2; and tautomers, solvates and pharmaceutically
acceptable salts thereof.
In a further preferred embodiment, said heteroaryl ring W is a 6-membered heteroaryl ring
containing one to four heteroatoms, wherein said atoms are solely N, and wherein
said 6-membered heteroaryl ring W is optionally substituted by 1 to 3 R8, wherein R8 is
independently at each occurrence halogen, preferably fluorine, -OH, C1-Csalkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, CHZCFs, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-
Cscycloalkyl, -NH2, NHCH3 or N(CH3)2; and tautomers, solvates and pharmaceutically
acceptable salts thereof.
In a r preferred embodiment, said 5- to 6-membered heteroaryl ring W is selected
from
F F F F
6’ 6” 6’ 6’ 6’
HEN N” HEN N” N” N’ N’
In a further very preferred embodiment, said aryl ring W is a 6-membered aryl
ring selected from
F F F F
%’ I?” 6’ m” [If
HEN N” HEN N” N” N” N”
In a further preferred embodiment, R1 or R2 is said 4- to 6-membered heterocyclic ring Z.
In a further preferred ment, said heterocyclic ring Z is a ted 5- to 6-
membered heterocyclic ring Z ning 1 to 2 heteroatoms independently selected from
N, O and S, optionally substituted by 1 to 3 R9; wherein R9 is independently at each
occurrence halogen, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, CH2F, CHF2, CF3, CHZCFs, C1-
Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-Cecycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9
substituents form together a bivalent residue —R10R11— selected from C1-Cgalkylene
optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CHZCH2-O-;
In a further preferred embodiment, said heterocyclic ring Z is a saturated 5- to 6-
membered heterocyclic ring Z selected from
III-F .13 N+ 06. N III—h HN Na...
F t I a s
2015/076192
“0*” it
Cl" H -I r
In an again further preferred embodiment, said heterocyclic ring Z is a saturated 5- to 6-
membered heterocyclic ring Z selected from
F r “a a“ H
F ‘a_.-"
t it J
or {—4 :1 ;’—‘~, ‘3'” ll
1m.-’ L-. :3,5
Ma- 0 I‘ll—h tale-F Hon
In a preferred embodiment, said heterocyclic ring Z is an oxazolidinyl optionally
tuted with halogen, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, CH2F, CHF2, CF3,
CHchs, C1-Czalkoxy, C1-CzalkoxyC1-Cgalkyl, =O, -NH2, NHCH3 or N(CH3)2.
In a further preferred embodiment, said heterocyclic ring Z is
if} kill;
In a further preferred embodiment, R1 or R2 is said OR”.
In a further preferred ment, said R12 is C1-Cgalkyl, CH2F, CHF2, CF3, CHZCHZF,
CHZCHFZ, CHZCFs, C1-Cgalkoxy, Cg-Cecycloalkyl, C1-Czalkylenecg-Cscycloalkyl; Cycle-P
or C1-CzalkyleneCycle-P, wherein Cycle-P represents a saturated 4- to ered
heterocyclic ring containing 1 to 2 heteroatoms independently selected from N, O and S,
optionally substituted by 1 to 2 R13, wherein R13 is independently at each occurrence
halogen, -OH, lkyl, CHZOH, CHZCHZOH, C1-szluoroalkyl, C1-Czalkoxy, C1-
CzalkoxyC1-Csalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-CzalkyleneCycle-Q, wherein
Cycle-Q represents 5- to 6-membered heteroaryl ring containing 1 to 2 heteroatoms
ndently selected from N, O and S, optionally substituted by 1 to 3 R14, wherein R14
is independently at each occurrence halogen, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, C1-
szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Cgalkyl, -NH2, NHCH3 or N(CH3).
In a further preferred ment, said R12 is C1-Cgalkyl, CH2F, CHF2, CF3, CHZCHZF,
CHZCHFZ, , C1-Cgalkoxy, Cg-Cecycloalkyl, C1-Czalkylenecg-Cscycloalkyl; Cycle-P
or C1-CzalkyleneCycle-P, wherein Cycle-P represents a saturated 4- to 6-membered
heterocyclic ring containing 1 to 2 heteroatoms independently selected from O and 8,
preferably from O, ally substituted by 1 to 2 R13, wherein R13 is independently at
each occurrence halogen, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, C1-szluoroalkyl, C1-
Czalkoxy, C1-CzalkoxyC1-Csalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl ring
containing 1 to 2 heteroatoms, wherein said heteroatoms are N, and wherein said
heteroaryl ring is optionally tuted by 1 to 3 R14, n R14 is ndently at each
occurrence n, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, C1-szluoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, -NH2, NHCH3 or N(CH3).
In an again further preferred embodiment, said OR12 is selected from
In a further preferred embodiment, R1 or R2 is said NR15R16.
In a further preferred embodiment, said R15 and R16 are independently of each other H,
C1-Cgalkyl, CHZOH, CHZCHZOH, C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl;
Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-P represents a saturated 4- to 6-
membered heterocyclic ring containing 1 to 2 heteroatoms independently selected from O
and 8, preferably from O, optionally substituted by 1 to 2 R13, wherein R13 is independently
at each occurrence halogen, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, C1-szluoroalkyl, C1-
Czalkoxy, C1-CzalkoxyC1-Csalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Cycle-Q represents 5- to ered aryl ring
containing 1 to 2 heteroatoms, wherein said heteroatoms are N, and wherein said
heteroaryl ring is optionally substituted by 1 to 3 R14, wherein R14 is ndently at each
occurrence halogen, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, C1-szluoroalkyl, C1-Czalkoxy,
C1-CzalkoxyC1-Csalkyl, -NH2, NHCH3 or N(CH3).
In a further red embodiment, said R15 and R16 are independently of each other H,
C1-Cgalkyl, CHZOH, CHZCHZOH, uoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl;
Cycle-P or C1-CzalkyleneCycle-P, wherein Cycle-P represents a saturated 4- to 6-
ed cyclic ring containing 1 to 2 atoms independently selected from O
and 8, preferably from O, optionally substituted by 1 to 2 R13, wherein R13 is independently
at each occurrence halogen, -OH, C1-Cgalkyl, CHZOH, OH, C1-szluoroalkyl, C1-
Czalkoxy, C1-CzalkoxyC1-Csalkyl, -NH2, NHCH3 or N(CH3); Cycle-Q or C1-
CzalkyleneCycle-Q, wherein Q represents 5- to 6-membered heteroaryl ring
ning 1 to 2 heteroatoms, wherein said heteroatoms are N, and wherein said
heteroaryl ring is optionally substituted by 1 to 3 R14, wherein R14 is independently at each
occurrence halogen, -OH, C1-Cgalkyl, CHZOH, CHZCHZOH, C1-szluoroalkyl, C1-Czalkoxy,
lkoxyC1-Csalkyl, -NH2, NHCH3 or N(CH3).
In an again further preferred embodiment, said NR15R16 is selected from
, l: H l: H
F . F l
4k].
Fix/m1 kai Ni 3.3%“:
3me1_
In another preferred embodiment of the t invention, said R1 and said R2 are
independently of each other a morpholinyl of formula (II)
WO 75130
l (H)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl optionally
substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-
Cgalkyl, ON, or C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —
R5R6— ed from C1-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II).
In another preferred embodiment of the present invention, said R1 and said R2 are
independently of each other a morpholinyl of formula (ll)
Rafi 1R4
l (H)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl optionally
substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-
Csalkyl, ON, or C1-Czalkyl; or R3 and R4 form together a bivalent residue —
R5R6— selected from C1-Csalkylene optionally substituted with 1 to 4 F, -CH2-,
-CH2-NH-CH2-, or any of the structures
A A-
wherein the arrows denote the bonds in formula (II);
with the provisos that
(a) when R1 is holinyl, ylmorpholinyl, ylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 3-aza-8—
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, 2-methylmorpholinyl,
3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]octyl, 3-azaoxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.1]octyl, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.1]octyl or
3-aza-8—oxabicyclo[3.2.1]octyl.
In a further red embodiment, said R1 is equal to said R2, and said R1 and said R2 are
independently of each other a morpholinyl of formula (ll)
Rsi 1R4
i (ll)
n the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl ally
substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, lkoxyC1-
Csalkyl, ON, or C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —
R5R6— selected from C1-Csalkylene optionally substituted with 1 to 4 F, -CH2-,
-CH2-NH-CH2-, or any of the ures
wherein the arrows denote the bonds in formula (II).
In a further preferred embodiment, said R1 is equal to said R2, and said R1 and said R2 are
independently of each other a morpholinyl of formula (II)
R3E j—R‘i
i (ll)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl optionally
substituted with one or two OH, C1-szluoroalkyl, C1-Czalkoxy, C1-CzalkoxyC1-
Csalkyl, ON, or C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —
WO 75130
R5R6— selected from C1-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II);
with the provisos that
(a) when R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 8—
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, 2-methylmorpholinyl,
3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]octyl, 3-aza-8—oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octy| or
3-aza-8—oxabicyclo[3.2.1]octyl.
In a further preferred ment of the t invention, said R1 and said R2 are
independently of each other a morpholinyl of formula (II)
R3— _R4
f (H)
n the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl, CHZOH,
OH, CH2F, CHF2, CF3, CHZCFs, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, ON, or
C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —R5R6— selected
from C1-Cgalkylene, preferably C1-Czalkylene, -CHZCF2-, F-, -CHZCFZCH2-,
-CH2-O-CH2-, H-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II).
WO 75130
In a further preferred embodiment of the present invention, said R1 and said R2 are
independently of each other a morpholinyl of formula (ll)
Rsi 1R4
I (ll)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, CHZCFs, C1-Czalkoxy, lkoxyC1-Csalkyl, ON, or
C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —R5R6— ed
from C1-Cgalkylene, preferably C1-Czalkylene, -CHZCF2-, -CHFCHF-, -CHZCFZCH2-,
-CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures
A A-
n the arrows denote the bonds in formula (II);
with the provisos that
(a) when R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 3-oxabicyclo[3.2.1]octy| or 3-aza-8—
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, 2-methylmorpholinyl,
3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]oct—8-y|, 3-aza-8—oxabicyclo[3.2.1]octy|, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, ylmorpholinyl,
octadeuteriomorpholinyl, 3-oxabicyclo[3.2.1]octy|, 8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or
3-aza-8—oxabicyc|o[3.2.1]octy|.
In a further preferred embodiment of the present invention, R1 is equal to R2, and said R1
and said R2 are a morpholinyl of formula (II)
I (ll)
wherein the arrow denotes the bond in formula (I); and
2015/076192
wherein R3 and R4 are independently of each other H, C1-Cgalkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, CHZCFs, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, ON, or
C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —R5R6— ed
from C1-Cgalkylene, preferably C1-Czalkylene, -CHZCF2-, -CHFCHF-, -CHZCFZCH2-,
-CH2-O-CH2-, H-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II).
In a further preferred embodiment of the present invention, R1 is equal to R2, and said R1
and said R2 are a morpholinyl of a (II)
R3— _R4
i (ll)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, CHZCFs, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, ON, or
C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —R5R6— selected
from C1-Cgalkylene, preferably lkylene, -CHZCF2-, -CHFCHF-, -CHZCFZCH2-,
-CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II);
with the provisos that
(a) when R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octy| or 8—
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, ylmorpholinyl,
3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]octy|, 3-aza-8—oxabicyc|o[3.2.1]octy|, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octy|, 3-aza-8—
yclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 3-oxabicyclo[3.2.1]oct—8—yl or
3-aza-8—oxabicyclo[3.2.1]octyl.
In another aspect and preferred embodiment, the present invention provides for a
compound of (I)
X’l/‘Nx2 {3% ,F
it a,
at “x3 “fits!
”a. ”flak
N“ “Ni-i2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and wherein
R1 and R2 are independently of each other a morpholinyl of formula (ll)
R3E —R4
l (H)
wherein the arrow denotes the bond in formula (I); and R1 is not equal to R2, and at least
one of said R1 and said R2 are a morpholinyl of formula (II),
R3— —R4
l ("l
n R3 and R4 are independently of each other C2-C3alkyl, CHZOH, CH2CH20H,
CH2F, CHF2, CF3, CH2CF3, C1-C2alkoxy, lkoxyC1-C3alkyl, ON, or C(O)O-C1-C2alkyl;
or R3 and R4 form together a bivalent residue —R5R6— selected from —CH2— or C3alkylene,
preferably —CH2—, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, H-CH2-, or
any of the structures
/ \ I \ ; wherein the arrows denote the bonds in formula (II).
Preferably, said R3 and R4 form er a nt residue —R5R6— selected from —
CH2— or C3alkylene, preferably —CH2—, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-
O-CH2-, -CH2-NH-CH2-, or any of the structures
f \ I \
In a further aspect and preferred embodiment, the t invention provides for a
compound of formula (I), wherein R1 and R2 are independently of each other said
morpholinyl of formula (II) and said 5- to 6-membered heteroaryl ring W, and ers,
solvates and pharmaceutically acceptable salts thereof.
In a further aspect and preferred embodiment, the present invention provides for a
compound of (l)
x'f/étl‘xz F“ /F
if L
3‘ N“ x3?“ “NE,,
W, Y
”m iijx
N NH2
(I)
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a linyl of formula (ll)
Rsi 1R4
i (ll)
wherein the arrow denotes the bond in formula (I); and
n R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, lkoxyC1-
C3alkyl, ON, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue—
R5R6— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a 5- to 6-membered heteroaryl ring W containing one to four heteroatoms
independently selected from N, O and S, optionally tuted by 1 to 3 R8, wherein
WO 75130
R8 is independently at each occurrence halogen, -OH, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, C3-C6cycloalkyl, -NH2, NHCH3 or N(CH3)2;
and prodrugs, metabolites, ers, solvates and pharmaceutically acceptable salts
f, preferably and tautomers, solvates and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the present invention provides for a compound of(|)
33,},W21“ ,3:.1 I
R 1,3
“m x,
N NH2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (II)
R3E j—R‘i
1 (ll)
wherein the arrow denotes the bond in formula (I); and
n R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, ON, or C(O)O-C1-C2alkyl; or R3 and R4 form er a bivalent residue—
R5R6— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a 5- to 6-membered heteroaryl ring W containing one to four atoms,
wherein said heteroatoms are solely N, and wherein said ered heteroaryl
ring W is optionally tuted by 1 to 3 R8, wherein R8 is independently at each
occurrence halogen, -OH, C1-C3alkyl optionally substituted with one or two OH, C1-
C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl, -NH2, NHCH3 or
N(CH3)2; and tautomers, solvates and pharmaceutically acceptable salts thereof.
Preferably, said 5- to 6-membered heteroaryl ring W containing one to four N is
optionally substituted by 1 to 3 R8, wherein R8 is independently at each occurrence
halogen, -OH, C1-C3alkyl, CHZOH, CH2CH20H, CH2F, CHF2, CF3, , C1-
C2a|koxy, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl, -NH2, NHCH3 or N(CH3)2;
and tautomers, solvates and pharmaceutically acceptable salts thereof.
In a further preferred embodiment, the t invention provides for a compound of(|)
X1’jkfx2 fix, w i:
Rum,l I
“it 3;
”NH;
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the o that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (ll)
Rsi 1R4
f (ll)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-C3alkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, ON, or
C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected
from C1-C3alkylene, preferably C1-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-,
-CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in a (II); and
(ii) a 5- to ered heteroaryl ring W containing one to four heteroatoms,
wherein said heteroatoms are solely N, and n said 5- to ered
aryl ring W is optionally substituted by 1 to 3 R8, wherein R8 is independently
at each occurrence halogen, -OH, C1-C3alkyl, CHZOH, CHZCHZOH, CH2F, CHF2,
CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, ycloalkyl, -NH2, NHCH3 or
N(CH3)2,
and tautomers, solvates and pharmaceutically able salts thereof.
In a further preferred embodiment, the present invention provides for a compound of(l)
x1 N x2 a, ,9
Rf ”3:3? RD“ “its!
““Nifikmi-iz
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (ll)
Rsi 1R4
i (ll)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are ndently of each other H, C1-C3alkyl, CHZOH,
0H, CH2F, CHF2, CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, ON, or
C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected
from C1-C3alkylene, preferably C1-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-,
-CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a 5- to 6-membered heteroaryl ring W containing one to four atoms,
wherein said heteroatoms are solely N, and wherein said 5- to 6-membered
heteroaryl ring W is optionally substituted by 1 to 3 R8, wherein R8 is independently
at each ence n, -OH, C1-C3alkyl, CHZOH, CH2CH20H, CH2F, CHF2,
CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl, -NH2, NHCH3 or
N(CH3)2;
and tautomers, solvates and pharmaceutically acceptable salts thereof.
In a further preferred embodiment, the present invention es for a nd of(l)
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and wherein R1 and R2 are independently of each
other said morpholinyl of formula (II) and said 5- to 6-membered heteroaryl ring W,
wherein said R1 and said R2 are independently of each other selected from
1 0 [:1 1;); ESL [Eli JEL 2:1;l
1:», E1 1:2} 1:}
IIIIII
I [a
T3113)” [:1 E? E3} [ELGH
rrrriir
{j} [:33 [:13 [:0]: (:3? [:36
+ i i i i
[TL/F [it]? [i114 [tilting Kills“
F F’ F F
[if if?” a “a
,.-' I I
HEN N H2“ M if [”3”
N” H”
N4Pf i‘ K N"
IN“ | "R hf hr
[5} HHH i M “an Ira} [.N
N Haw” H r H “rm M'
and tautomers, solvates and pharmaceutically acceptable salts thereof.
In a further preferred ment, the present invention provides for a compound of (I)
it; at 1/
R? (X3 Mix“ Mutt
"“N "est—i2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and wherein R1 and R2 are independently of each
other said morpholinyl of formula (II) and said 5- to 6-membered aryl ring W,
wherein said R1 and said R2 are independently of each other selected from
D II} a i} Eli
[il‘ jfik ,ENJ; WINL r Li +
[i iii 5 0 '3"
t [f-Ti’tletle”i 0‘“
i i i i i
®$#$%$$
TLVWWWW
99%???thl i it
Erik? [$15]; [flick (irks, [it]?
[Eh [31> 1:}: [3:0 (:33,
l l +
and tautomers, es and ceutically acceptable salts thereof.
In a further aspect and red embodiment, the present invention provides for a
compound of formula (I), wherein R1 and R2 are independently of each other said
morpholinyl of formula (II) and said saturated 4- to 6-membered heterocyclic ring Z, and
tautomers, solvates and pharmaceutically acceptable salts thereof.
In a further aspect and preferred embodiment, the present invention provides for a
compound of (l)
WO 75130
gwx g:
XI; “1-4:? X2
if L l/
R? NXS‘ \{W “31“}; “‘N'fi’i‘wi—i2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are ndently of each other
(i) a morpholinyl of formula (ll)
Rsi 1R4
i (ll)
wherein the arrow denotes the bond in formula (I); and
n R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
l, ON, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —
R5R6— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a saturated 4- to 6-membered heterocyclic ring Z containing 1 to 3 heteroatoms
independently selected from N, O and S, optionally substituted by 1 to 3 R9; wherein
R9 is independently at each occurrence halogen, -OH, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, C3-C6cycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9 substituents form
together a bivalent residue —R10R11— selected from C1-C3alkylene optionally
substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-;
and prodrugs, metabolites, tautomers, solvates and pharmaceutically able salts
thereof, preferably and tautomers, es and pharmaceutically acceptable salts thereof.
In a further aspect and preferred embodiment, the present ion provides for a
compound of (I)
WO 75130
gwx g:
XI; “1-4:? X2
if at l/
R? NXS‘ \{W “31“}; i‘wi—i2
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (ll)
Rsi 1R4
i (ll)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, ON, or C1-C2alkyl; or R3 and R4 form together a bivalent residue—
R5R6— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a saturated 4- to ered heterocyclic ring Z containing 1 to 3 heteroatoms
independently ed from N, O and S, optionally substituted by 1 to 3 R9; wherein
R9 is independently at each occurrence halogen, -OH, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, C3-C6cycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9 substituents form
together a nt residue —R10R11— selected from C1-C3alkylene ally
substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-;
and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts
thereof, preferably and tautomers, solvates and pharmaceutically acceptable salts thereof;
with the provisos that
(a) when R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuterio—4-morpholinyl, 8-azaoxabicyc|o[3.2.1]oct—8-y| or 3-aza-8—
WO 75130
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, 2-methylmorpholinyl,
3-methylmorpholinyl, octadeuterio—4-morpholinyl, 8—aza
yclo[3.2.1]oct—8-y|, 3-aza-8—oxabicyclo[3.2.1]octy|, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuterio—4-morpholinyl, 8—azaoxabicyclo[3.2.1]oct—8-y|, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, uteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or
8—oxabicyclo[3.2.1]octy|.
In a preferred embodiment, the present invention provides for a compound of(|)
L 1%
x? x2 fr:
kl 1
R1 ”X3 KEV/"wry
N Mir—l2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (II)
R3E j—R‘i
i (ll)
wherein the arrow denotes the bond in a (I); and
wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally
tuted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, ON, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —
R5R6— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a saturated 5- to ered heterocyclic ring Z containing 1 to 2 heteroatoms
independently selected from N, O and S, optionally substituted by 1 to 3 R9; wherein
R9 is ndently at each occurrence halogen, -OH, C1-C3alkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, CH2CF3, lkoxy, lkoxyC1-C3alkyl, C3-
Cecycloalkyl, =O, -NH2, NHCH3 or 2; or two R9 substituents form together a
bivalent residue 1— selected from C1-C3alkylene optionally substituted with 1
to 4 F, -CH2-O-CH2- or CH2-O-;
and tautomers, solvates and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the present invention provides for a compound of(|)
xfijgxz F», “or:
.13, ,XL :l
RT x3 E NYa
, filli‘x
N NH2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (ll)
Rsi 1R4
f (H)
wherein the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally
substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-
C3alkyl, ON, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue—
R5R6— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-,
-CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a saturated 5- to 6-membered heterocyclic ring Z containing 1 to 2 atoms
independently selected from N, O and S, optionally substituted by 1 to 3 R9; wherein
WO 75130
R9 is independently at each occurrence halogen, -OH, C1-C3alkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, , C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, C3-
Cecycloalkyl, =O, -NH2, NHCH3 or 2; or two R9 substituents form er a
bivalent residue —R10R11— selected from C1-C3alkylene optionally substituted with 1
to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-;
and tautomers, solvates and pharmaceutically acceptable salts thereof;
with the provisos that
(a) when R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuterio—4-morpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 3-aza-8—
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, 2-methylmorpholinyl,
3-methylmorpholinyl, octadeuterio—4-morpholinyl, 8—aza
oxabicyclo[3.2.1]octyl, 3-aza-8—oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-
piperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuterio—4-morpholinyl, 8—azaoxabicyclo[3.2.1]octyl, 8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or
3-aza-8—oxabicyclo[3.2.1]octyl.
In a further preferred ment, the present invention provides for a compound of(l)
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (ll)
KN7R4
¢ (ll)
n the arrow denotes the bond in formula (I); and
wherein R3 and R4 are independently of each other H, lkyl, CHZOH,
CH2CH20H, CH2F, CHF2, CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, ON, or
C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected
from C1-C3alkylene, preferably C1-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-,
-CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a saturated 5- to 6-membered heterocyclic ring Z containing 1 to 2 heteroatoms
independently selected from N, O and S, optionally substituted by 1 to 3 R9; wherein
R9 is independently at each occurrence halogen, -OH, C1-C3alkyl, CHZOH,
CH2CH20H, CH2F, CHF2, CF3, , C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, C3-
Cecycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9 substituents form together a
bivalent residue —R10R11— selected from C1-C3alkylene ally substituted with 1
to 4 F, -CH2- or -O-CH2CH2-O-;.
and tautomers, solvates and pharmaceutically acceptable salts f.
In a further preferred embodiment, the present invention provides for a compound of(l)
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and
R1 and R2 are independently of each other
(i) a morpholinyl of formula (ll)
Rsi 1R4
l (H)
n the arrow s the bond in formula (I); and
wherein R3 and R4 are independently of each other H, C1-Cgalkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, CHZCFs, C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, ON, or
C(O)O-C1-Czalkyl; or R3 and R4 form together a bivalent residue —R5R6— selected
from C1-Cgalkylene, preferably C1-Czalkylene, 2-, -CHFCHF-, -CHZCFZCH2-,
-CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures
wherein the arrows denote the bonds in formula (II); and
(ii) a saturated 5- to 6-membered heterocyclic ring Z containing 1 to 2 heteroatoms
independently selected from N, O and S, optionally substituted by 1 to 3 R9; wherein
R9 is independently at each occurrence halogen, -OH, C1-Cgalkyl, CHZOH,
CHZCHZOH, CH2F, CHF2, CF3, , C1-Czalkoxy, C1-CzalkoxyC1-Csalkyl, Cs-
Cecycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9 substituents form together a
bivalent residue —R10R11— selected from C1-Csalkylene optionally substituted with 1
to 4 F, -CH2-O-CH2- or -O-CHZCH2-O-;.
and ers, solvates and pharmaceutically acceptable salts thereof;
with the os that
(a) when R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octy| or 3-aza-8—
oxabicyclo[3.2.1]octyl; then R2 is not 4-morpholinyl, 2-methylmorpholinyl,
3-methylmorpholinyl, octadeuteriomorpholinyl, 3-
yclo[3.2.1]octy|, 3-aza-8—oxabicyc|o[3.2.1]octy|, 4-piperazinyl, 4-
piperazinyl, or 4-thiomorpholinyl;
(b) when R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octy|, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
rpholinyl; then R1 is not holinyl, ylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or
3-aza-8—oxabicyc|o[3.2.1]octy|.
In a further preferred embodiment, the present invention provides for a compound of (l)
I at I
R? (X3 Mix“ Matt
"“N "hit—i2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and wherein R1 and R2 are independently of each
other said morpholinyl of formula (II) and said saturated 4- to 6-membered cyclic
ring 2, wherein said R1 and said R2 are independently of each other selected from
«:3» fit [It 1:} Ct Us
I][lIJ\[1{/[j\,[j
'i 'i i 'i 'i i
izi D :3 C; a;
“”[il‘ t 1V t t f ‘t J’
i 'i i i
\th tgi’ gr“ 5;; E? tgiw
tileW 6% w M
a 633 “:5 tint WP “i?
is i" i it i l t
rrrriir
[3- Ci 0 1:} Q Q
{E} (p: [21:0 [@1130 [i]? [@103
o o a U D
E’4?ij E jfi/F I: kl: E JW’U‘“ l:
F i FF i a ilk?“
: Cit-1"" Ci><:H* USN N—h HMS“;
—r~4 N-h N N+ I22} iii—h
w._.r -_x n_x -._r
ff; H,
r—t EL I M '3 NJ
18 N" H m
S New '3
a r o DH H
L“0"” it
3:- D NJ
In a further preferred ment, the present invention provides for a compound of (I)
I at I
R? (X3 Mix“ Matt
"“N "hit—i2
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the o that at least two
of X1, X2 and X3 are N; Y is N or CH; and wherein R1 and R2 are independently of each
other said morpholinyl of formula (II) and said saturated 4- to 6-membered heterocyclic
ring 2, wherein said R1 and said R2 are independently of each other selected from
«:3» fit [It 1:} Ct Us
I][lIJ\[1{/[j\,[j
'i 'i i 'i 'i i
izi D :3 C; a;
“”[il‘ t 1V t t f ‘t J’
i 'i i i
\th tgi’ gr“ 5;; E? tgiw
tileW 6% w M
a 633 “:5 tint WP “i?
is i" i it i l t
wvthtv
[3- G 0 1:} Q Q
{E} [21]: [21:0 [@1130 £th [$10.3
a D E} U D
E’4?ij E jfi/F I: kl: E JW’U‘“ l:
F t FF t [3 wk?“
: Chi-l" Ct>6???- DSH N—h HMS“;
—r~4 N—a- N N+ I22} Nan
w._r -_.a* -_x -._r
ff; H,
x—t EL I M '3 NJ
a r 0 DH H
L“0’" it
3:- D NJ
with the provisos that
(a) when R1 is 4-morpholinyl, 2-methyImorpholinyl, 3-methyImorpholinyl,
octadeuterio—4-morpholinyl, 8—aza0xabicyclo[3.2.1]oct-8—y| or 3-aza-8—
yclo[3.2.1]octy|; then R2 is not 4-morpholinyl, 2-methyImorpholinyl,
3-methyImorpholinyl, octadeuterio—4-morpholinyl, 8—aza
yclo[3.2.1]oct—8-y|, 3-aza-8—oxabicyclo[3.2.1]octy|, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl;
(b) when R2 is holinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,
octadeuterio—4-morpholinyl, 8-azaoxabicyclo[3.2.1]oct—8-y|, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-
thiomorpholinyl; then R1 is not 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.1]octyl or
3-aza-8—oxabicyclo[3.2.1]octy|.
In a further red embodiment, the present invention es for a compound of(l)
Lza F
1‘: UM” “QTY
X31 Mi
wherein
X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two
of X1, X2 and X3 are N; Y is N or CH; and wherein R1 and R2 are independently of each
other said morpholinyl of formula (II) and said saturated 4- to 6-membered heterocyclic
ring Z, wherein said R1 and said R2 are independently of each other selected from
[TL 12L 1T1; “(TL (TL,
”ETA“ET3”- YTTr [Tim £31»
Tib$$$TiTElflEfi
{3} {in €13“ {I} Ella
3%YfffpEll,
0‘ FF
W» i ,
i l $74? l El)“
[l]? [ljri Elli“ [le [le
[:19 [31> [311:0 [:33
+ l i i +
F Chi—r- r “a
to>Cl-«l-h U N Na-
F ‘~_f
M Ma- :3 Pal—h “1*
~._.r -_.r a_»* DJ} U
fl r1
1' '3'
NH N’i‘" '3
CI NJ
A ‘3" L DAM”
OH H '3 H t l
In a further aspect and preferred embodiment, the present invention provides for a
compound of a (I), wherein R1 and R2 are independently of each other said
morpholinyl of formula (II) and said OR12.
In a further aspect and preferred embodiment, the present invention provides for a
compound of formula (I), wherein R1 and R2 are ndently of each other said
morpholinyl of formula (II) and said NR15R16.
In another preferred embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 3-aza-8—
oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-thiomorpholinyl.
In another red embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 3-aza-8—
oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
linyl, octadeuteriomorpholinyl, 3-oxabicyclo[3.2.1]octyl, 3-aza-8—
oxabicyclo[3.2.1]octyl, razinyl, 4-methylpiperazinyl, or 4-thiomorpholinyl,
and X1, X2 and X3 are N; and ers, solvates and ceutically acceptable salts
thereof. Preferably Y is N or CH; R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 3-aza-8—
oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl, 8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-thiomorpholinyl;
and tautomers, solvates and pharmaceutically acceptable salts thereof.
In a further red embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl-
4-morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl or 8—
oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, yl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]octyl, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-thiomorpholinyl,
and X1 and X3 are N, and X2 is CH; and tautomers, solvates and pharmaceutically
acceptable salts thereof. Preferably Y is N or CH; R1 is 4-morpholinyl, 2-methyl
linyl, 3-methylmorpholinyl, octadeuteriomorpholiny|, 8—aza
oxabicyclo[3.2.1]octyl or 3-aza-8—oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-
methylmorpholinyl, 3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]octyl, 8—oxabicyclo[3.2.1]octyl, 4-piperaziny, 4-
methylpiperazinyl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically
able salts thereof.
In a preferred embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]oct—8—yl or 3-aza-8—
oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]oct—8—yl, 3-aza-8—
yclo[3.2.1]octyl, 4-piperazinyl, ylpiperazinyl, or 4-thiomorpholinyl,
and X1 and X2 are N, and X3 is CH; and tautomers, solvates and pharmaceutically
acceptable salts thereof. Preferably, Y is N or CH; R1 is 4-morpholinyl, 2-methyl
morpholinyl, 3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]oct—8—yl or 3-aza-8—oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-
morpholinyl, 3-methylmorpholinyl, octadeuteriomorpholinyl, 3-
oxabicyclo[3.2.1]oct—8—yl, 3-azaoxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically
acceptable salts thereof.
In a preferred embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
morpholinyl, octadeuteriomorpholinyl, 8—azaoxabicyclo[3.2.1]oct—8—yl or 3-aza-8—
oxabicyclo[3.2.1]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl
linyl, uteriomorpholinyl, 3-oxabicyclo[3.2.1]oct—8—yl, 3-aza-8—
oxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-methylpiperazinyl, or 4-thiomorpholinyl,
and X2 and X3 are N, and X1 is CH; and tautomers, solvates and pharmaceutically
acceptable salts thereof. Preferably, Y is N or CH; R1 is 4-morpholinyl, 2-methyl
morpholinyl, 3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
oxabicyclo[3.2.1]oct—8—yl or 3-aza-8—oxabicyclo[3.2.1]octyl; and R2 is holinyl, 2-
methylmorpholinyl, 3-methylmorpholinyl, octadeuteriomorpholinyl, 8—aza
yclo[3.2.1]oct—8—yl, 3-azaoxabicyclo[3.2.1]octyl, 4-piperazinyl, 4-
methylpiperazinyl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically
able salts thereof.
In a red embodiment, the compound of formula (I) is selected from the group
consisting of
- 4-(difluoromethyl)—5-(4,6-dimorpholino-1,3,5-triazinyl)pyridinamine;
- 4-(difluoromethyl)—5-(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octanyl)-1,3,5-
triazinyl)—4-(difluoromethyl)pyridinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)morpholino-1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyridinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)morpholino-1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyrimidinamine;
- 5-(4,6-bis((S)—3-methylmorpholino)-1,3,5-triazinyl)(difluoromethyl)pyridinamine;
- -bis((S)—3-methylmorpholino)—1,3,5-triazinyl)—4-(difluoromethyl)pyrimidin
amine;
- (S)—4-(difluoromethyl)(4-(3-methylmorpholino)—6-morpholino-1,3,5-triazinyl)pyridin-
2-amine;
- (S)—4-(difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazin
y|)pyrimidinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)—3-methylmorpholino)—1,3,5-triazinyl)—
4-(difluoromethyl)pyridinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)—3-methylmorpholino)—1,3,5-triazinyl)—
4-(difluoromethyl)pyrimidinamine;
- 4-(difluoromethyl)(4-morpholino(piperazinyl)-1,3,5-triazinyl)pyridinamine;
- 4-(difluoromethyl)(4-morpholino(piperazinyl)-1,3,5-triazinyl)pyrimidin
amine;
- (S)—4-(difluoromethyl)(4-(3-methylmorpholino)—6-(piperazinyl)-1,3,5-triazin
y|)pyridinamine; and
- (S)—4-(difluoromethyl)(4-(3-methylmorpholino)—6-(piperazinyl)-1,3,5-triazin
y|)pyrimidinamine;
and tautomers, solvates and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the compound of formula (I) is selected from the group
ting of
- 4-(difluoromethyl)—5-(2,6-dimorpholinopyrimidinyl)pyridinamine;
- fluoromethyl)—2,6-dimorpholino-[4,5'-bipyrimidin]-2'-amine;
- 5-(6-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octan
imidinyl)—4-(difluoromethyl)pyridinamine;
- 5-(6-(3-oxaazabicyclo[3.2.1]octanyl)morpholinopyrimidinyl)—4-
(difluoromethyl)pyridinamine;
- 6-(3-oxaazabicyclo[3.2.1]octanyl)-4'-(difluoromethyl)—2—morpholino-[4,5'-
bipyrimidin]—2'-amine;
- 5-(2,6-bis((S)—3-methylmorpholino)pyrimidinyl)—4-(difluoromethyl)pyridinamine;
- 4'-(difluoromethyl)-2,6-bis((S)—3-methylmorpholino)-[4,5'-bipyrimidin]-2'-amine;
- (S)—4-(difluoromethyl)(6-(3-methylmorpholino)morpholinopyrimidinyl)pyridin
amine;
- (S)—4'-(difluoromethyl)(3-methylmorpholino)—2-morpholino-[4,5'-bipyrimidin]-2'-amine;
- 5-(2—(3-oxaazabicyclo[3.2.1]octanyl)morpholinopyrimidinyl)—4-
(difluoromethyl)pyridinamine;
- 2-(3-oxaazabicyclo[3.2.1]octanyl)-4'-(difluoromethyl)—6-morpholino-[4,5'-
bipyrimidin]—2'-amine;
- (S)—4-(difluoromethyl)(2-(3-methylmorpholino)morpholinopyrimidinyl)pyridin
amine; and
- -(difluoromethyl)(3-methylmorpholino)morpholino-[4,5'-bipyrimidin]-2'-amine;
and ers, solvates and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the compound of formula (I) is selected from the group
consisting of luoromethyl)(6-morpholino(piperazinyl)pyrimidinyl)pyridin
amine and 4'-(difluoromethyl)—6-morpholino(piperaziny|)-[4,5'-bipyrimidin]—2'-amine;
and tautomers, solvates and ceutically acceptable salts thereof.
In a preferred embodiment, the compound of formula (I) is selected from the group
consisting of 4-(difluoromethyl)—5-(4,6-dimorpholinopyrimidinyl)pyridinamine and 4'-
(difluoromethyl)—4,6-dimorpholino-[2,5'-bipyrimidin]-2'-amine; and tautomers, solvates and
pharmaceutically acceptable salts thereof.
In a preferred embodiment, the compound of formula (I) is selected from the group
ting of
- 4-(difluoromethyl)—5-(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxa-8—azabicyclo[3.2.1]octanyl)-1,3,5-
triazinyl)—4-(difluoromethyl)pyridinamine;
- 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)morpholino-1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyridinamine;
- 5-(4,6-bis((S)—3-methylmorpholino)—1,3,5-triazinyl)—4-(difluoromethyl)pyrimidin
amine;
- (S)—4-(difluoromethyl)(4-(3-methylmorpholino)—6-morpholino-1,3,5-triazinyl)pyridin-
2-amine;
- 4-(difluoromethyl)(4-morpholino(piperazinyl)-1,3,5-triazinyl)pyrimidinamine;
- 4-(difluoromethyl)—5-(4,6-dimorpholino-1,3,5-triazinyl)pyridinamine; and
- (S)—4-(difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazin
y|)pyrimidinamine;
and tautomers, solvates and pharmaceutically acceptable salts thereof.
red are compounds wherein R1 and R2 are 4-morpholinyl.
Likewise preferred are compounds wherein R1 and R2 are 3-aza-8—oxabicyclo[3.2.1]oct
Likewise red are compounds wherein R1 and R2 are (S)—3-methylmorpholinyl.
Likewise preferred are compounds wherein R1 is 4-morpholinyl and R2 is (S)—3-methyl
morpholinyl.
Likewise preferred are compounds wherein R1 is 4-morpholinyl and R2 is 3-aza-8—
oxabicyclo[3.2.1]octyl.
Likewise red are compounds n R1 is 4-morpholinyl and R2 is 4-piperazinyl.
Likewise preferred are compounds wherein R1 is 4-morpholinyl and R2 is 4-thio-
morpholinyl.
More preferred are compounds of formula (I) n R1 and R2 are 4-morpholinyl, and Y
is CH.
Equally preferred are compounds of formula (I) wherein R1 and R2 are holinyl, and
Y is N.
More preferred are compounds of formula (I) wherein R1 and R2 are 3-aza-8—
oxabicyclo[3.2.1]octyl, and Y is CH.
More preferred are compounds of formula (I) wherein R1 and R2 are (S)—3-methyl
linyl, and Y is N.
More preferred are compounds of formula (I) wherein R1 is 4-morpholinyl and R2 is 4-
piperazinyl, and Y is N.
More preferred are compounds of formula (I) wherein R1 is 4-morpholinyl and R2 is (S)
methylmorpholinyl, and Y is CH.
More preferred are compounds of formula (I) wherein R1 is 4-morpholinyl and R2 is 3-aza-
8-oxabicyclo[3.2.1]octyl, and Y is N.
More preferred are compounds of formula (I) wherein R1 is methylmorpholinyl and
R2 is 8—oxabicyclo[3.2.1]octyl, and Y is CH.
More preferred are compounds of formula (I) wherein R1 is (S)—3-methylmorpholinyl and
R2 is 4-piperazinyl, and Y is CH.
Likewise preferred are compounds of formula (I) n R1 is (S)—3-methylmorpholinyl
and R2 is 4-piperazinyl, and Y is N.
More preferred are compounds of formula (I) wherein R1 is 4-morpholinyl and R2 is 4-
thiomorpholinyl, and Y is CH.
Likewise preferred are compounds of formula (I) wherein R1 is 4-morpholinyl and R2 is 4-
rpholinyl, and Y is N.
Even more preferred are compounds of formula (I), wherein X1, X2 and X3 are N.
Likewise preferred are compounds of formula (I), wherein X1 and X3 are N, and X2 is CH.
Most preferred are the ing compounds shown by formula:
(The names of the corresponding structures were produced using ChemDraw Ultra,
version 13.0.1 as well as lower and upper software ns thereof, CambridgeSoft
Corp., Cambridge MA).
2015/076192
Compound 1:
4-(difluoromethyl)—5-(4,6-dimorpholino—1,3,5-triazin-2—y|)pyridinamine
Compound 2:
4-(difluoromethyl)—5-(4,6-dimorpholino—1,3,5-triazin-2—y|)pyrimidin-2—amine
Compound 3:
gt: F
N N
0@*flN/
-(4-(3-oxaazabicyclo[3.2.1]octan-8—y|)(3-oxa-8—azabicyclo[3.2.1]octan-8—y|)—1 ,3,5-
triazin-2—y|)(difluoromethyl)pyridin-2—amine
Compound 4:
N N |\
CK) N/ NH2
-(4-(3-oxaazabicyclo[3.2.1]octany|)morpho|ino-1,3,5-triazin-2—yl)—4-
(difluoromethyl)pyridinamine
WO 75130
Compound 5:
4F}:
N1 N
0QNxNéng| AN
-(4-(3-oxaazabicyclo[3.2.1]octany|)morpho|ino-1,3,5-triazin-2—y|)—4-
(difluoromethyl)pyrimidin-2—amine
Compound 6:
-(4,6-bis((S)—3-methylmorpholino)—1,3,5-triazin-2—yI)(difluoromethyl)pyridinamine
Compound 7:
5-(4,6-bis((S)—3-methylmorpholino)—1,3,5-triazin-2—yI)(difluoromethyl)pyrimidin-2—amine
Compound 8:
(S)—4-(difluoromethyl)(4-(3-methy|morpholino)—6-morpho|ino-1,3,5-triazin-2—y|)pyridin
amine
Compound 9:
(S)—4-(difluoromethyl)(4-(3-methy|morpholino)—6-morpho|ino-1,3,5-triazin-2—
y|)pyrimidin-2—amine
Compound 10:
|\ N
O(ZN N/ NH2
-(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)—3-methy|morpholino)—1,3,5-triazin-2—yl)—
4-(difluoromethyl)pyridinamine
Compound 11:
F F
N \N
(g ;N/kN/ \N
O 42
-(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)—3-methy|morpholino)—1,3,5-triazin-2—yl)—
4-(difluoromethyl)pyrimidin-2—amine
Compound 12:
4-(difluoromethyl)(4-morpho|ino(piperaziny|)-1,3,5-triazin-2—y|)pyridinamine
Compound 13:
jig“! F F
N N \N
0d l
N/)\NH2
4-(difluoromethyl)(4-morpho|ino—6-(piperaziny|)-1,3,5-triazin-2—y|)pyrimidin-2—amine
Compound 14:
(S)—4-(difluoromethyl)(4-(3-methy|morpholino)—6-(piperaziny|)-1,3,5-triazin-2—
yl)pyridin-Z-amine
Compound 15:
(S)—4-(difluoromethyl)(4-(3-methy|morpholino)—6-(piperaziny|)-1,3,5-triazin-2—
yl)pyrimidin-Z-amine
nd 16:
N\F F
N N |\
N/NH2
4-(difluoromethyl)—5-(2,6-dimorpholinopyrimidinyl)pyridin-2—amine
Compound 17:
4'-(difluoromethyl)—2,6-dimorpholino—[4,5'-bipyrimidin]—2'-amine
Compound 18:
N N |\
0d N/ NH2
4-(difluoromethyl)—5-(4,6-dimorpholinopyrimidin-2—yl)pyridin-2—amine
Compound 19:
I“ F
N ‘N/
0d N/)\NH2
4'-(difluoromethyl)—4,6-dimorpholino—[2,5'-bipyrimidin]-2'-amine
Compound20:
luoromethyl)(4-morpho|ino—6-thiomorpholino—1,3,5-triazin-2—y|)pyridinamine
Compound21:
4-(difluoromethyl)(4-morpho|ino—6-thiomorpholino—1,3,5-triazin-2—y|)pyrimidin-2—amine
Further preferred are the following compounds
Compound 22:
-(6-(3-oxaazabicyclo[3.2.1]octan-8—y|)(3-oxa-8—azabicyclo[3.2.1]octan-8—
yl)pyrimidinyl)—4-(difluoromethyl)pyridinamine
Compound 23:
/ \ ~
/ tttt
difluoromethl ridinamine
Compound 24:
2- 3-oxaazabic Clo 3.2.1 octan-8— | -4'- rometh | mor holino— 4 5'—bi rimidin -
2'—amine
Compound 25:
(:1.,,,
: N \
r AN/| N \
0d 3
N/ NH2
-(2,6-bis((S)—3-methylmorpholino)pyrimidinyl)—4-(difluoromethyl)pyridinamine
Compound 26:
4'-(difluoromethyl)-2,6-bis((S)—3-methylmorpholino)—[4,5'-bipyrimidin]—2'-amine
2015/076192
Compound 27:
[31.1,]
AN/1 N \
0d §
N/ NH2
(S)—4-(difluoromethyl)(6-(3-methy|morpholino)—2—morpholinopyrimidinyl)pyridin
amine
Compound 28:
(S)—4'-(difluoromethyl)—6-(3-methylmorpholino)—2—morpho|ino-[4,5'-bipyrimidin]—2'-amine
Compound 29:
5-(4-(8—Oxaazabicyclo[3.2.1]octanyl)(8—oxaazabicyclo[3.2.1]octanyl)—1 ,3,5-
triazin-2—y|)(difluoromethyl)pyridin-2—amine
Compound 30:
-[4,6-bis(2,2—dimethylmorpholinyl)—1,3,5-triazin-2—yI](difluoromethyl)pyridinamine
Compound 31:
(S)—4-(difluoromethyl)(2—(3-methy|morpholino)—6-morpholinopyrimidinyl)pyridin
amine
nd 32:
///////////////
(S)—4'-(difluoromethyl)—2—(3-methylmorpholino)—6-morpho|ino-[4,5'-bipyrimidin]-2'-amine
Compound 33:
4-(difluoromethyl)—5-[4-[(28,6R)—2,6-dimethylmorpholinyl]—6-[(3R)—3-methylmorpholin
y|]-1,3,5-triazin-2—yl]pyridinamine
Compound 34:
W,»O\r
N? f F
mg” N FL;
ix 7LMMMMMMMm‘:
-[4,6-bis[(2R,6S)—2,6-dimethylmorpholiny|]-1,3,5-triazin-2—yI](difluoromethyl)pyridin-
2—amine
Compound 35:
6-amino(difluoromethyl)pyridy|]—6-morpho|ino-1,3,5-triaziny|]morpho|in
Compound 36:
4-[4-[2—amino(difluoromethyl)pyrimidinyl]—6-morpholino—1,3,5-triaziny|]morpho|in-
3-one
Compound 37:
0 o
\ I
r“ if
-[4,6-bis(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazin-2—yl]—4-
(difluoromethyl)pyridinamine
Compound 38:
4-(difluoromethyl)—5-[4-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—6-(3-oxa-8—
azabicyclo[3.2.1]octan-8—y|)—1,3,5-triazin-2—yl]pyridinamine
WO 75130
Compound 39:
-[4,6-bis(3,3-dimethylmorpholinyl)—1,3,5-triazin-2—y|]—4-(difluoromethyl)pyridinamine
Compound 40:
-[4,6-bis[(3R,58)—3,5-dimethylmorpholiny|]-1,3,5-triazin-2—y|]—4-(difluoromethyl)pyridin-
2—amine
Compound 41:
-[4,6-bis[(3R)—3-methylmorpholinyl]—1,3,5-triazin-2—yI](difluoromethyl)pyridin
amine
Compound 42
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyI)—6-morpho|ino-1,3,5-triazin-2—
yI]pyridin-Z-amine
Compound 43:
6-amino(difluoromethyl)pyridy|]—6-[(3R)—3-methylmorpholinyl]—1,3,5-triazin-2—
y|](difluoromethyl)pyridinamine
Compound 44:
4-(difluoromethyl)—5-[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methylmorpholin
y|]-1,3,5-triazin-2—y|]pyridinamine
Compound 45:
N“ “NHZ
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-[(3R)—3-methylmorpholinyl]—
1,3,5-triazin-2—y|]pyridinamine
Compound 46:
(”O\
3 {Wk
0m x» a /,F
1 *2 T?‘ T
,/ m ,.»”‘~x Ng/x \\ x»! 433‘?
gx N
/) g {A}.
N, x “x
N NH;
4-(difluoromethyl)[4-[(3R)—3-(methoxymethyl)morpholinyl]—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triazin-2—y|]pyridinamine
Compound 47:
4-(difluoromethyl)—5-[4-(3,7-dioxa-Q-azabicyclo[3.3.1]nonan-9—y|)—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triazin-2—y|]pyridinamine
nd 48:
NAN F 03%EN
A NJKNH
(4S,5R)—3-[4-[2—amino(difluoromethyl)pyrimidinyl]—6-morpho|ino-1,3,5-triazin-2—yI]
(hydroxymethyl)—5-methyI-oxazo|idinone
Compound 49:
HO“; NAN F F
.......fiN
0&0 |
N N H2
(4S,5R)—3-[6-[2—amino(difluoromethyl)pyrimidinyl]—2—morpho|ino-pyrimidiny|]
(hyd roxymethyl)methy|—oxazo|idinone
Compound 50:
4-(difluoromethyl)[4-[(3R)—3-methy|morpholinyl](3-oxaazabicyclo[3.1.1]heptan-
6-y|)-1,3,5-triazin-2—yl]pyridinamine
Compound 51:
F F
J5 '
O N” NH
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](6-oxaazabicyclo[3.1.1]heptan-
3-y|)-1,3,5-triazinyl]pyridinamine
Compound 52:
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(1R,4R)—2-oxa
azabicyclo[2.2.1]heptany|]—1,3,5-triazinyl]pyridinamine
Compound 53:
[1*ti
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(1S,4S)—2-oxa
azabicyclo[2.2.1]heptany|]—1,3,5-triazinyl]pyridinamine
Compound 54:
[:1v
1it?“
DVD 5
IN/ NH2
5-[4,6-bis[(3R)—3-ethy|morpholinyl]—1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine
Compound 55:
[N19
N’I’L‘NF F
ad I
N NH2
-[4,6-bis(8—oxaazaspiro[3.5]nonany|)—1,3,5-triazinyl]—4-(difluoromethyl)pyridin-2—
amine
Compound 56:
[wk/F
N23: F
0QN’lfiwkfg,.N
-bis[(3R)—3-isopropy|morpholinyl]—1,3,5-triaziny|](difluoromethyl)pyridin
amine
Compound 57:
NAP F F
F a.
F rlJ N K
F M” NH
2
4-[6-amino(difIuoromethyl)pyridy|]-N-methy|—6-[(3R)—3-methy|morpholinyl]—N-
(2,2,2-trifluoroethyl)—1,3,5-triazinamine
Compound 58:
[0ML
[1%]in F
N RN “x
F H I
F f
4-[6-amino(difIuoromethyl)pyridy|][(3R)—3-methy|morpholinyl]—N-(2,2,2-
trifluoroethyl)—1,3,5-triazinamine
Compound 59:
4-[6-amino(difIuoromethyl)pyridy|]-N-(cyc|opropy|methyl)[(3R)—3-methy|morpholin-
4-y|]-1,3,5-triazinamine
Compound 60:
A F
F 3:” T”a
N NHR
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2,2,2-trifluoroethoxy)—1,3,5-
triazinyl]pyridinamine
nd 61:
A F F
N’ N
FjflOJxN | a
F N/ NH2
-[4-(2,2-difluoroethoxy)—6-[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine
Compound 62:
[0ML
N'FL‘P F F
« [*4er
0 NI NH2
-[4-[(3aR,6aS)—1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrro|y|][(3R)—3-methy|morpholin-
4-y|]-1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine
CompoundO63:
-[4-[(4aS,7aR)—2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-0]pyrrolyl]—6-[(3R)—3-
methylmorpholinyl]—1,3,5-triaziny|](difluoromethyl)pyridinamine
Compound 64:
{WEE
4-(difluoromethyl)—5-[4-(4,4-difluoropiperidyl)[(3R)—3-methy|morpholinyl]—1 ,3,5-
nyl]pyridinamine
Compound 65:
Er:L
N H-
31;?1
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](2-oxaazaspiro[3.5]nonany|)—
1,3,5-triazinyl]pyridinamine
Compound 66:
NAN F F
(LN’JQL‘N I
N N H»:
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R,58)—3,5-dimethylmorpholin
y|]-1,3,5-triaziny|]pyridinamine
Compound 67:
0 N’L‘M F F
£11”le, & I
I I
0 x
“V” N NH2
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[(3R)—3-(methoxymethyl)morpho|in-
4-y|]-1,3,5-triazinyl]pyridinamine
Compound 68:
Ho NAN F F
(I A I N N “a
0V1 |
N NH2
[(3R)—4-[4-[6-amino(difluoromethyl)pyridy|]—6-(3,3-dimethylmorpholinyl)—1 ,3,5-
triazinyl]morpholinyl]methanol
Compound 69:
Ni‘L‘N F F
,JQ. '
G?N N a
o M” N Hz
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-(3,7-dioxa-9—
azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazinyl]pyridinamine
nd 70:
V/ “V” N NH2
5-[4-(4-cyclopropylpiperaziny|)(3,3-dimethylmorpholinyl)—1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine
Compound 71:
[HIV
51-me F
”NANfiN | “QWNH/l I
N NH»,
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)[4-(2-methoxyethyl)piperaziny|]-
1,3,5-triazinyl]pyridinamine
Compound 72:
[33¢
A F F
NilNANAEEN’N
N N Ha:
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)(oxetany|oxy)—1,3,5-triazin
y|]pyridinamine
Compound 73:
[a[‘ij
<3: ”NV N N
NH2
luoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-[(3S)—tetrahydrofuranyl]oxy-
1,3,5-triazinyl]pyridinamine
Compound 74:
0:: N‘AN F F
VANO/AAN I Na
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-[(3R)—tetrahydrofuranyl]oxy-
1,3,5-triazinyl]pyridinamine
Compound75:
[aMJV
01 Ng‘rlq F F
K “”51
N NH;
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-tetrahyd ropyranyloxy—1 ,3,5-
triazin-2—y|]pyridinamine
nd 76:
L if”
I? x
w F F
mg) E J
4-(difluoromethyl)—5-[4-(3,3-dimethylmorpholinyl)—6-(1,1-dioxo-1,4-thiazinanyI)-1,3,5-
triazin-2—y|]pyridinamine
Compound 77:
HO, TM
,/ F» /F
J '? u
r N “N” ”I x
Ox/J [\ Nari“
1 0 NH2
[(3R)—4-[4-[6-amino(difluoromethyl)pyridyl]—6-[(3R)—3-methylmorpholinyl]—1 ,3,5-
triazinyl]morpholinyl]methanol
Further preferred compounds are
Compound
[0ML
A F F
(lN’JflmfiN r If] Od'hr’ ,
N NH2
4-(difluoromethyl)[4-[(3R,5R)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methylmorpholin
y|]-1,3,5-triazin-2—yl]pyridinamine
Compound:
4-(difluoromethyl)[4-[(3S,58)—3,5-dimethylmorpholinyl]—6-[(3R)—3-methy|morpholin
y|]-1,3,5-triaziny|]pyridinamine
Compound:
N” NF
@111km0
4-(difluoromethyl)[4-morpho|ino(3-oxa-9—azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazin-
2-yl]pyridinamine
Compound:
‘: F
:2“*fii
-[4,6-bis(3-oxa-9—azabicyclo[3.3.1]nonan-9—yI)-1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine
Compound:
F NAN]: F
I“ I“
HN N” M” NH
5-[4-[6-amino(difluoromethyl)pyridy|]—6-(3,7-dioxa-9—azabicyclo[3.3.1]nonan-9—y|)—
1,3,5-triazinyl]—4-(difluoromethyl)pyridinamine
Compound:
(NIKE;N “N “x
INX NHZ
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](4-morpho|inopiperidy|)—1,3,5-
triazinyl]pyridinamine
Compound:
-[4-(4-cyclopropylpiperaziny|)[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine
Compound:
V/ V’ NH2
-[4-(4-Cyclopropylpiperaziny|)[(3S,5R)—3,5-dimethylmorpholinyl]—1,3,5-triazin
y|](difluoromethyl)pyridinamine
Compound:
[0ML
[4ng F F
“r N I“:
N N H2
luoromethyl)[4-[4-(2-methoxyethyl)piperaziny|][(3R)—3-methy|morpholinyl]—
1,3,5-triazinyl]pyridinamine
2015/076192
Compound:
F F
N” N
(W? N I“
‘QAx/Nx/ NI) m H2
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-[4-(2-
methoxyethyl)piperaziny|]-1,3,5-triaziny|]pyridinamine
Compound
’ENL
NAN F F
N M “a
rxll N [“ng
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholiny|](4-morpho|inopiperidy|)—
1,3,5-triazinyl]pyridinamine
Compound:
4-(difluoromethyl)—5-[4-(1,1-dioxo-1,4-thiazinanyl)[(3R)—3-methy|morpholinyl]—
1,3,5-triazinyl]pyridinamine
Compound:
(ENL
N‘LL‘N F F
,qu |
0f“? N p("
LII‘M/ N
o MH2
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-(1,1-dioxo-1,4-thiazinan
y|)-1,3,5-triazinyl]pyridinamine
Compound:
01 N‘L‘rlal F F
k 0%
M! NH?
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|]tetrahydropyranyloxy-1,3,5-
triazinyl]pyridinamine
Compound:
0’1 I‘J F F
K OANKEELHf
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-tetrahyd ropyranyloxy-
1,3,5-triazinyl]pyridinamine
Compound:
[0ML
DAN “x
M NH:
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|][(3S)—tetrahydrofuranyl]oxy-
1,3,5-triazinyl]pyridinamine
Compound:
[0ML
0‘1. Am F F
K/fo-_ I
KN “a
M NH“
4-(difluoromethyl)[4-[(3R)—3-methy|morpholinyl][(3R)—tetrahydrofuranyl]oxy-
1,3,5-triazinyl]pyridinamine
Compound:
N’l‘
OAN a
N/ NH...
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholiny|][(3S)—tetrahydrofuran
-1,3,5-triazinyl]pyridinamine
Compound:
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholinyl]—6-[(3R)—tetrahyd rofuran
y|]oxy-1,3,5-triazinyl]pyridinamine
Compound:
N”N[HEP
51le
N NH2
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](oxetanyloxy)—1,3,5-triazin
y|]pyridinamine
Compound:
we:|/
N N Ha.
4-(difluoromethyl)[4-[(3S,5R)—3,5-dimethylmorpholiny|](oxetanyloxy)—1,3,5-
triazinyl]pyridinamine
Compound:
/EN]\
HAN F F
Ax '
0.2744 n “a
0" M MHZ
4-(difluoromethyl)[4-[(3R,58)—3,5-dimethylmorpholinyl]—6-(3,7-dioxa-9—
azabicyclo[3.3.1]nonan-9—y|)—1,3,5-triazinyl]pyridinamine
Compound:
3-[4-[6-amino(difluoromethyl)pyridyl]—6-[(3R,58)—3,5-dimethylmorpholinyl]—1 ,3,5-
nyl]oxazolidinone
Compound:
A: F F
N N
N N a
0 Hf NH
2
-(4-((1R,2R,48,5S)—7-oxa-9—azatricyclo[3.3.1.02:4]nonan-9—yl)((2R,4S)—7-oxa-9—
azatricyclo[3.3.1.02*4]nonanyI)-1,3,5-triazinyl)—4-(difluoromethyl)pyridinamine
Compound:
‘7‘ F
F F F
N I, N
F |
N N “H
U N NH2
5-[4,6-bis(6,6-difluorooxa-8—azabicyclo[3.2.1]octan-8—y|)—1,3,5-triazinyI]
(difluoromethyl)pyridinamine
1 10
Compound:
«33;:
F F F
N Am
N N “a
F I
or N NHE
-[4,6-bis(6,7-difluorooxa-8—azabicyclo[3.2.1]octan-8—y|)—1,3,5-triazinyI]
oromethyl)pyridinamine
Compound:
[0ML
NfiLN F F
E? | a
K N a
HEM N N NH2
-[4-(6-aminopyridyl)[(3R)—3-methy|morpholinyl]—1,3,5-triaziny|]
(difluoromethyl)pyridinamine
Compound:
EDMl
F F A F F
N , IN
N am “x.
| |
, f
N N
NHz
4-(difluoromethyl)—5-[4-[4-(difluoromethyl)pyridy|]—6-[(3R)—3-methy|morpholinyl]—
1,3,5-triazinyl]pyridinamine
Compound:
NA? F F
x “N “a:
| |
, I,
N N ran-12
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](3-pyridy|)-1,3,5-triazin
y|]pyridinamine
WO 75130
Compound:
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|]pyraziny|-1,3,5-triazin
y|]pyridinamine
Compound:
[1:L
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-pyrazolyl)—1,3,5-triazin
y|]pyridinamine
Compound:
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1H-pyrazolyl)—1,3,5-triazin
y|]pyridinamine
Compound:
4-(difluoromethyl)[4-[(3R)—3-methy|morpholiny|](1,2,4-triazoly|)—1,3,5-triazin
y|]pyridinamine
Compound:
wfil4*\lel
4-(difluoromethyl)[4-[(3R)—3-methylmorpholinyl]—6-(1H-1,2,4-triazolyl)—1,3,5-
triazinyl]pyridinamine
Compound:
I/01L
M :l‘l
4-(difluoromethyl)[4-[(3R)—3-methylmorpholinyl]—6-(2H-tetrazolyl)—1,3,5-triazin
y|]pyridinamine
Preparation of compounds of the invention
The compounds of the invention may be synthesized by synthetic routes that include
processes analogous to those well known in the chemical arts, particularly in light of the
description contained herein. The starting materials are generally available from
commercial sources or are readily prepared using methods well known to those skilled in
the art.
In preparing compounds of the invention, protection of remote functionality (e.g., y
or secondary amine) of intermediates may be ary. The need for such protection will
vary depending on the nature of the remote functionality and the conditions of the
preparation methods. le amino-protecting groups include tert—butyloxycarbonyl
(BOC), bis-tert—butyloxycarbonyl or dimethylaminomethylenyl. The need for such
protection is readily ined by one skilled in the art. For a l description of
protecting groups and their use, see T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 1991.
Methods of tion
In the methods of preparing the compounds of this invention, it may be advantageous to
separate reaction products from one another and/or from ng materials. The desired
products of each step or series of steps are separated and/or purified to the desired
degree of homogeneity by the ques common in the art. Typically such separations
involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation,
sublimation, or chromatography. Chromatography can involve any number of methods
including, for example: reverse-phase and normal phase; high, medium and low re
liquid chromatography s and apparatus; small scale analytical; and preparative
thin or thick layer chromatography, as well as techniques of small scale thin layer and
flash chromatography.
Selection of appropriate methods of separation depends on the nature of the materials
involved, for example, presence or absence of polar functional groups in chromatography,
stability of materials in acidic and basic media in multiphase extraction, and the like. One
skilled in the art will apply techniques most likely to e the d separation.
Examples
The Examples are intended to illustrate the present invention without restricting it.
The chemical reactions described in the es may be readily adapted to prepare a
number of other lipid kinase tors of the invention, and ative methods for
preparing the compounds of this invention are deemed to be within the scope of this
invention. For example, the synthesis of non-exemplified compounds according to the
invention may be successfully performed by modifications apparent to those skilled in the
art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents
known in the art other than those described, and/or by making routine modifications of
reaction conditions. Alternatively, other reactions disclosed herein or known in the art will
be recognized as having applicability for preparing other compounds of the invention.
As a rule, 1” NMR and mass spectra have been obtained for the compounds prepared. In
the Examples described below, unless ise indicated, all temperatures are set forth
in degrees Celsius (°C). Reagents were purchased from commercial suppliers such as
Sigma Aldrich, chem, Acros, Lancaster, TCl or Maybridge, and were used without
r purification unless otherwise indicated. The reactions setforth below were done
generally under a positive pressure of nitrogen or with a drying tube (unless otherwise
stated) in anhydrous solvents, and the on flasks were typicallyfitted with rubber
septa for the introduction of substrates and reagents via syringe. Glassware was oven
dried. Column chromatography was performed using Merck silica gel. 1” NMR spectra
1” NMR spectra
were recorded on a Bruker instrument operating at400 MHz. were
obtained for solutions in various ated solvents such as CDCI3, (CD3)ZSO, CD30D or
(CD3)2CO. The chemical shift 6 values were ed in ppm and corrected to the signal of
the deuterated solvents (7.26 ppm for CDCI3) or TMS (0 ppm). 19F NMR spectra were
calibrated relative to CFCI3 (6 = 0 ppm) as external standard. 19F NMR a were
recorded 1H-decoupled. When peak multiplicities are reported, the ing abbreviations
are used: s (singlet), d (doublet), t (triplet), m (multiplet), quint (quintet), br (broadened).
Coupling constants, when given, are reported in Hertz (Hz). MALDI-ToF Mass a
(MS) have been obtained on a Voyager-DeTM Pro measured in m/z.
The following iations are used hereinafter: BSA (bovine serum albumin),
DMSO (dimethyl sulfoxide), ESI (electronspray ionization), HCI (hydrochloric acid),
M (molar), MALDI (Matrix-assisted Laser Desorption/Ionization), MS (mass spectrometry),
PBS hate buffered saline), TLC (thin layer chromatography).
Preparation of Intermediate Compounds
The following methods were used to prepare the intermediates compounds used to
produce nds of a (I).
Method 1: 8- 4- 3-oxa-8—azabic clo 3.2.1 octan l chloro-1 3 5-triazin l oxa
azabicyclo|3.2.1|octane (i1 )
Cl N
NJ§N —> N/KN
A ‘
/ /
Cl N Cl «3%N N Cl
3-Oxa-8—azabicyclo[3.2.1]octane-HC| (Advanced ChemBlocks lnc, product number A—861,
2.00 g, 13.4 mmol, 2.0 eq.) and N,N-diisopropylethylamine (4.80 mL, 27.6 mmol, 4.1 eq.)
are charged into a flask and dissolved in dichloromethane (20 mL). The flask is placed in
an ice bath and the solution subsequently cooled down to 0 °C. This solution is then
added dropwise to a solution of cyanuric chloride in dichloromethane (20 mL) at 0 °C. The
resulting reaction mixture is stirred overnight, while it is allowed to warm up to room
temperature. Additional dichloromethane (100 mL) is added and the organic layer is
washed with a saturated aqueous solution of sodium bisulfate. The organic layer is then
dried over ous sodium sulfate, filtered and the solvent is evaporated under reduced
pressure. Purification by flash chromatography hexane/ ethyl e 4:1) gives the
desired intermediate i1 as a colorless solid (79% yield). 1H NMR (400 MHz, CDCI3):
8 4.70-4.54 (m, 4 H), 3.80-3.58 (m, 8 H), 2.14-1.89 (m, 8 H); MS (MALDI):
m/z = 338.4 ([M+H]+).
Method 1 is also used for the ation of the following ediate compounds i2 to
HO, and intermediates i79 to i81.
Reagent Structure NMR MS
(:1 1H NMR (400 MHz, CDCI3): MS (MALDI):
8 3.78 (m, 8 H), 3.70 (m, m/z = 287.6
8 H). ([M+Hl+)-
1H NMR (400 MHz, CDCI3): 8
4.75-4.56 (m, 2 H), 4.34-4.30
(m, 2 H), 3.94 (dd, 2.0)., =
12.0 Hz, 3.0,), = 4.0 Hz, 2 H),
3.74 (d, 2.0,), =12.0 Hz, 2 H),
MS (MALDI):
E 1, 3.63 (dd, 2.0,), = 12.0 Hz,
m/z = 314.4
I2 3.0,), = 4.0 Hz, 2 H), 3.49 (dt,
([M+Hl+)-
2JH), = 12.0 Hz,
3./.,,.,= 4.0 Hz, 2 H), 3.25 (dt,
2JH), = 12.0 Hz,
3.0,), = 4.0 Hz, 2 H), 1.31 (d,
3.0)., = 8.0 Hz, 6 H).
KAN. Lax/K 1H NMR (400 MHz, : MS (MALDI):
i4 L )8- 6 3.81-3.72 (m, 8 H), 3.43 (s, m/z = 342.5
“N”!1‘” l E]: $4
H 4 H ), 1.43 (br s, 12 H). ([M+H]+ ).
(“f N,- 8w 6.0%
1H NMR (400 MHz, CDCI3):
6 4.75-4.56 (m, 2 H), 4.34-
4.30 (m, 2 H), 3.94 (dd,
2.1),), = 12.0 Hz,
(”OAK 3.1),), = 4.0 Hz, 2 H), 3.74 (d,
.208. ml“ 2.1),), = 12.0 Hz, 2 H), 3.63 MS (MALDI):
i5 L f}\ Nag-N (dd, 2.1),), = 12.0 Hz, m/z = 314.3
g (LN, *"N”1i”‘"c: 3JH,H= 4.0 Hz, 2 H), 3.49 (dt, ([M+H]+).
j 2.1),), = 12.0 Hz,
06-...
3.1),), = 4.0 Hz, 2 H), 3.25 (dt,
2.1),), = 12.0 Hz,
3.1),), = 4.0 Hz, 2 H), 1.31 (d,
3.1),), = 8.0 Hz, 6 H).
1H NMR (400 MHz, :
,0...
M0“ )Nk :4.40-4.37 (m, 4 H), 3.74 (d, MS (MAI—DI):
J”’” = 11'6 HZ’ 4 H)’
i6 J 5%. m/z = 342.8
WNW“k .1. Z ff“ 3.53 (dd, 3JH,H= 11.6 Hz,
H ([M+H]+)
( W N’ W? '
2.1),), = 4.0 Hz, 4 H), 1.26 (d,
O‘w/K 3.1),), = 6.9 Hz, 12 H).
(0‘50
(01 ;::5? M,
%{8// :,N - ( r S’ )’ - ( rs,
i7 m/z = 370.3
2 H), 4.12-4.06 (m,8 H),
N ,NAN‘C’LWC: ([M]+)_
H 6:”???.2 3.92-3.83 (m, 8 H).
1H NMR (400 MHz,
,0. ....
4 H), 3.85-3.75 (m, 4 H),
.8 [, k m/z = 342 3
I I
(”#3,
x x /'
g f‘f 3.48-3.45 (m, 2 H), .34
([W)
(m, 2 H), 3.14-3.09 (m, 2 H),
1.72 (m, 4 H), 0.82 (m, 6 H).
,« 1H NMR (400 MHz,
L» i ‘ “'3 (MALD'):
.434. (003)280): 6 , 8 H),
i9 ka» NAN ”7/2 = 366-7
3.351-3.48 (m, 4 H), 2.46-
H .N-N/Lx‘N» 8Q 2.38 (m, 4 H), 2.20-2.16 (m, ([M] )-
09. 4 H), 1.73-1.66 (m, 4 H).
1H NMR (400 MHz,
~ (CD3)280): 6 4.40-4.25 (m,
MS (MALD'):
o «- k 2 H), 4.20-4.05 (m, 2 H), 4.08
“0 [NR N}. ”7/2 = 370-4
(m, 2 H), 3.95 (m, 2 H), 3.83
H J (m, 4 H), 3.08 (m, 2 H), 2.30 (WIT)-
(m, 2 H), 0.98 (m, 6 H), 0.48
(m, 6 H).
\[,O 1/ 1H NMR (400 MHz, CDCI3):
a MS (MALDI):
\f f 6 4.59-4.31 (m, 4 H), 3.66-
i79 m/z= 342.4
ii ii 1.
\wa/ .
3.46 (m, 4 H), 2.70 (m, 4 H),
([M+H]+).
1.14 (m, 12 H).
0x " [Sf/1H NMR (400 MHz, CDCI3): 6 MS (MALDI)_'
‘ ”
3.73-3.64 (m, 8 H), 3.57 (s,
I80_ m/z=342.3
$1M) 2H) 35”, . s, 2H) 114(, . s,
([M+H1+ ).
12 H).
206 1H NMR (400 MHz, CDCI3):
.08, 6 4.41 (br s, 4 H), 4.32- MS (MALDI):
i81 4.16 (m, 4 H), .10 (m, m/z = 338.4
4 f
fi 4 H), 1.99-1.84 (m, 4 H), ([M+H]+)
1.84-1.67 (m, 4 H).
1 18
Method 2: 2,4-dichloromorpholino—1,3,5-triazine (H1)
0 D
i: EN] [if]
N f 'f' MAN _,.
21 KNACl _C,|/J\H‘NN‘fII\E|
To a solution of cyanuric chloride (18.1 g, 0.100 mol, 1.0 eq.) in dichloromethane (200 mL)
is dropwise added a cold solution of morpholine (17.4 g, 0.200 mol, 2.0 eq.) at — 78 °C
over 2 hours. The resulting mixture is allowed to warm to 0 °C with stirring and mixed with
an ice cold saturated solution of sodium ate in water. The phases are separated and
the organic phase is washed with half concentrated brine dried over sodium sulfate and
evaporated to yield the title compound i11 as a colorless solid. 1H NMR (400 MHz,
CDCI3): 8 3.90-3.86 (m, 4 H), 3.77-3.72 (m, 4 H).
Method 3: 8- 4-chloromor holino—1 3 5-triazin l oxaazabic clo 3.2.1 octane
f” f“
(\N N/ C! (\N N/ CI
CV 0d
H1 "2
3-Oxaazabicyclo[3.2.1]octane-HC| (Advanced ChemBlocks lnc, product number A—861,
200 mg, 1.34 mmol, 1.1 eq.) and N,N-diisopropylethylamine (470 uL, 2.69 mmol, 2.1 eq.)
are charged in a flask and dissolved in ethanol (3 mL). The flask is placed in an ice bath.
A solution of nd H1 (300 mg, 1.28 mmol, 1.0 eq.) in ethanol (2 mL) is added to the
above on at 0 °C. The ing mixture is stirred overnight, while allowing it to warm
up to room temperature. Deionized water (20 mL) is added and the aqueous layer is
extracted with ethyl acetate (3 x 30 mL). The combined organic layer is dried over
anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure.
Purification by flash chromatography hexane / ethyl e 9:1 —> 8:2) gives the
desired intermediate i12 as a ess solid (78% yield). 1H NMR (400 MHz, CDCI3):
1 19
6 4.69-4.56 (m, 2 H), 3.86-3.59 (m, 12 H), 2.12-1.91 (m, 4 H); MS (MALDI):
m/z = 312.7 ([M+H]+).
Method 3 is also used for the preparation of the following intermediate compounds i13 to
i16.
Reagent Structure NMR
0 1H NMR (400 MHz, CDCI3): 6 .61 (m,
o LN)», 1 H), 4.34—4.31 (m,1 H), 3.96—3.92 (m,1 H),
i13 [N] MAW 3.79—3.70 (m, 9 H), 3.65-3.61 (m,1 H), 3.51—
" l
H kN/1'1L661 3.45 (m,1 H), 3.29—3.21 (m, 1 H), 1.36—
’’’’’’’ 1.30 (d, , = 6.9 Hz, 3 H).
0:: ,ON ,,/"
1 l
:l,WOWL, W 1H NMR (400 MHz, CDCI3): 6 3.79—3.71 (m,
_14 {.N/ .
I ,,
L. 3 NAN 12 H), 3.46 (m, 4 H), 1.48 (s, 9 H).
S A, ,4 ,1...
1“ ” “‘N’ “c:
ohm/l
fax N] 1H NMR (400 MHz, CDCI3): 6 4.12-3.98 (m,
i15 lW/l MEN 4 H), 3.84-3.70 (m, 4 H), 3.70-3.62 (m, 4 H),
H ”a. MEL. fig» 2.66 2.56 (m,4H)._
{,6 N N, C:
A)... L611 1H NMR (400 MHz, CDCI3): 6 3.77 (m, 4 H),
i16 L k Nag,“ 3.68-3.63 (m, 8 H), 3.44 (s, 2 H), 1.44 (s,
it A A Mi 6 H).
{1 N” N (:1
Method 4: S 4 6-dichloro-1 3 5-triazin l meth lmor holine i17
To a solution of cyanuric de (450 mg, 2.44 mol, 1.0 eq.) in dichloromethane (4 mL) is
slowly added a solution of (S)—3-methylmorpholine (Activate Scientific, product number
AS3424, 0.28 mL, 2.44 mol, 1.0 eq.) and triethylamine (0.35 mL, 2.51 mol, 1.02 eq.) in
dichloromethane (2 mL) at — 50 °C. The resulting mixture is stirred for 2 hours at — 50 °C,
then allowed to warm to 0 °C with stirring and mixed with an ice cold saturated solution of
sodium bisulfate in water. The phases are separated and the organic phase is washed
with brine dried over sodium e and evaporated to yield the title compound H? as a
colorless solid (95% yield). 1H NMR (400 MHz, CDCI3): 8 4.78-4.69 (m, 1 H), 4.43-4.39 (m,
1 H), 3.98-3.96 (m, 1 H), .76 (m, 1 H), 3.67-3.65 (m, 1 H), 3.51-3.47 (m, 1 H), 3.40-
3.37 (m, 1 H), 1.36 (m, 3 H).
Method 5: 8— 4-chloro S meth lmor holino 1 3 5-triazin loxa
azabicyclo|3.2.1|octane (i18)
3-Oxa-8—azabicyclo[3.2.1]octane-HC| (Advanced ChemBlocks lnc, product number A—861,
383 mg, 2.55 mmol, 1.1 eq.) and N,N-diisopropylethylamine (1.0 mL, 5.60 mmol, 2.4 eq.)
are charged in a flask and dissolved in ethanol (4 mL). The flask is placed in an ice bath.
A solution of nd i1? (580 mg, 2.33 mmol, 1.0 eq.) in ethanol (2 mL) is added to the
above solution at 0 °C. The resulting mixture is d for 4 hours, while allowing it to
warm up to room temperature. Deionized water(20 mL) is added and the aqueous layer is
extracted with ethyl acetate (3 x 30 mL). The combined c layer is dried over
anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure.
Purification by flash chromatography (cyclohexane/ ethyl acetate 9:1 —> 8:2) gives the
2015/076192
desired ediate i18 as a colorless solid (88% yield). 1H NMR (400 MHz, CDCI3):
8 4.75-4.52 (m, 3 H), 4.37-4.24 (m, 1 H), 3.95-3.92 (m, 1 H), 3.73-3.70 (m, 3 H), 3.64-3.61
(m, 3 H), 3.52-3.42 (m, 1 H), 3.29-3.17 (m, 1 H), 2.11-1.89 (m, 4 H), 1.31 (m, 3 H).
Method 6: tert—but l4- 4 6-dichloro-1 3 5-triazin l i erazinecarbox late i19
To a cooled (- 50 oC) solution of cyanuric chloride (1.0 g, 5.42 mmol, 1.0 eq.) in
dichloromethane (4 mL) is added dropwise a solution of tert—butyl piperazine
carboxylate (Sigma, product number 343536, 1.02 g, 5.48 mmol, 1.01 eq.) and
triethylamine (0.767 mL, 5.53 mmol, 1.02 eq.) in dichloromethane (2 mL). The resulting
reaction mixture is stirred at - 50 °C for 4 hours. A saturated aqueous solution of sodium
ate (10 mL) and dichloromethane (20 mL) are added. The mixture is transferred to a
separating funnel. The organic layer is separated, washed with a saturated aqueous
solution of sodium bisulfate (20 mL), dried over anhydrous sodium sulfate, filtered and
then the t is evaporated under reduced pressure to give pure intermediate HQ
(80% yield). 1H NMR (400 MHz, CDCI3): 8 3.88-3.85 (m, 4 H), 3.53-3.51 (m, 4 H), 1.49 (m,
9 H).
Method 7: tert—but l 4- 4- 8-azabic clo 3.2.1 8- l chloro-1 3 5-triazin
yl)piperazinecarboxylate (i20)
Ow, ,/O\“ x” 03.1% «OX
:3, i a; l/
l J f j
N N‘
i —. A
Di; ”if Ni l
CI mN" Cl [’fN RN"? or
0:31
I19 i20
3-Oxa-8—azabicyclo[3.2.1]octane-HC| (Advanced ChemBlocks lnc, product number A—861,
235 mg, 1.57 mmol, 1.0 eq.) and N,N-diisopropylethylamine (592 uL, 3.14 mmol, 2.1 eq.)
are charged in a flask and dissolved in ethanol (6 mL). The flask is placed in an ice bath.
A solution of compound HQ (500 mg, 1.5 mmol, 1.0 eq.) in ethanol (2 mL) is added to the
above solution at 0 °C. The resulting e is d overnight, while allowed to warm up
to room temperature. Deionized water (10 mL) is added and the aqueous layer is
extracted with ethyl acetate (3 x 30 mL). The combined organic layer is dried over
anhydrous sodium sulfate, filtered and the solvent is ated under reduced pressure.
Purification by flash chromatography (cyclohexane/ ethyl acetate 8:2) gave the d
intermediate i20 as a colorless solid (77% yield). 1H NMR (400 MHz, CDCI3): 8 4.68-
4.60 (m, 2 H), 3.76-3.70 (m, 6 H), 3.64-3.62 (m, 2 H), 3.47-3.45 (m, 4 H), 2.08-1.95 (m,
4 H), 1.48 (br s, 9 H); MS (MALDI): m/z = 411.8 ([M+H]+).
Method 7 is also used for the preparation of the following ediate compound i21.
Reagent Structure NMR MS
1H NMR (400 MHz, 00013):
84.76-4.61 (m,1 H), 4.35-4.30
09... x04. , (m, 1 H), 3.94 (dd, 2./.,,.,= 12 Hz,
AR, 3JH,H= 4.0 Hz, 1 H), 3.76-3.72
o ) ] MS (MALDI):
(m, 5 H), 3.65 (dd, 2 /
_ JHH: 12 Hz,
.21 m/z= 399.1
N I" if
<5 3,;H,H= 4 0 H 1H) 351344 -
N) 3’ - Z, , . .
2 ([M+H] )-
{f/mN MN?” NC: (m, 5 H), 3.25 (dt, JH,H= 12 HZ,
o...,/~j 3JH,H= 4.0 Hz, 1 H), 1.48 (s,
9 H), 1.30 (d, 3JH,H= 8.0 Hz,
3 H).
{.49.
Cl Cl KN)
,1%?
,,,,,, ”O A... ,1)?
12:14—th ,1) +111-
01” ” ‘N
N” \01 g (N “N! “NW“? Cl N" 1
O\,,,,,, Lu“ 0 L /O
122 .23
Trichloropyrimidine (Manchester Organics, product number Y17832, 11.2 g,
61 mmol, 1.0 eq.), N,N-diisopropylethylamine (23.3 mL, 134.2 mmol, 2.2 eq.) and
morpholine (11.7 mL, 134.2 mmol, 2.2 eq.) are charged in a flask and ved in ethanol
(120 mL). The flask is equipped with a refluxed condenser and placed in an oil bath
preheated at 100 °C. The reaction mixture is stirred at this temperature for 18 hours. After
this time, the reaction mixture is cooled down to room temperature and volatiles are
removed under reduced pressure. The resulting mixture is dissolved in dichloromethane
(100 mL) and washed twice with an aqueous solution of sodium bisulfate (2 x 80 mL). The
organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure using a rotary ator. Products i22 and i23 are isolated by flash
chromatography on silica gel (cyclohexane / ethyl acetate 3:1 9 1:1). The product
fractions are pooled and evaporated to yield i22 as a colorless powder (13.8 g, 80%) and
i23 as a colorless powder (2.2 g, 13% yield).
4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine (i22): 1H NMR (400 MHz, CDCI3): 8 5.85 (s,
1 H), 3.71-3.75 (m, 12 H), 3.52-3.55 (m, 4 H); MS ): m/z: 285.4 ([M+H]+).
4,4'-(2-chloropyrimidine-4,6-diyl)dimorpholine (i23): 1H NMR (400 MHz, CDCI3): 8 5.38 (s,
1 H), .76 (m, 8 H), 3.52-3.54 (m, 8 H); MS (MALDI): m/z: 285.2 ([M+H]+).
Method 9: 8- 4- 3-oxaazabic clo 3.2.1 octan | chloro rimidin | oxa
azabicyclo|3.2.1|octane (i24)
c; KNEE}
/»*"j??b «”01 L
ll .3 + EU —* 1” 1
or N c: g Wm,“ ”N , ‘0;
0.1/
A solution of2,4,6-trichloropyrimidine (0.676 mL, 5.88 mmol, 1.0 eq.), 8-
azabicyclo[3.2.1]octane hloride (1.76 g, 11.8 mmol, 2.0 eq.), and MN-
diisopropylethylamine (4.10 mL, 23.5 mmol, 4.0 eq.) in ethyl acetate (18 volumes) is
heated for 16 hours (100 °C). Then, the solvent is removed under reduced pressure and
the residue is ved in dichloromethane (60 s) and washed with a saturated
s sodium ate (3 x 60 volumes). The organic layer is dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure. Purification by column
chromatography on silica gel (cyclohexane / ethyl acetate 3:1 9 1:1) affords the desired
intermediate i24 as a colorless solid (1.23 g, 62%).1H NMR (400 MHz, CDCI3): 8 5.80 (s,
1 H), 4.59 (s, 2 H), 4.35 (m, 2 H), 3.76 (13.11,), = 10.8 Hz, 4 H), 3.59 (d, 2.11,), = 10.8 Hz,
4 H), 2.03 (m, 8 H); MS (MALDI): m/z = 337.7 ([M+H]+).
Method 9 is also used for the preparation of the following ediate compound i25.
Reagent Structure NMR MS
1H NMR (400 MHz, CDCI3): MS (MALDI): m/z
8 5.83 (s, 1 H), 4.64-4.57 (m, = 313.6 ([M+H]+).
[/1011 1 H), 4.27 (dd, 3.1),), = 2.4 Hz,
0 2‘11”” 2JH.H = 13.5 Hz, 1 H), 4.20-4.11
”5 [N] 3 51/114. (m, 1 H), .87 (m, 3 H),
H (£2311 “Néf'x‘cs 3.77-3.63 (m, 4 H), 3.56-3.46 (m,
‘1"!
2 H), 3.26-3.15 (m, 2 H), 1.28 (d,
3.1.1,.4 = 3.2 Hz, 3 H), 1.27 (d,
3.1.1,.4 = 3.2 Hz, 3 H).
Method 10: 4- 4 6-dichloro rimidin l mor holine i26 and 4- 2 loro rimidin
yl)morpholine (i2?)
,/O\.,
iii 33‘ L J
1”}? + E ,l ————-—-——-» 11 + t
or" "“N‘Acs {:13 (”N ‘1 N? “C: N; 19.]
0.1/3 Cl/ N”; “‘0;
i26 i27
To a solution of trichloropyrimidine (14.0 mL, 122 mmol, 1.0 eq.) in EtOH (150 mL)
is added a solution of morpholine (11.2 mL, 256 mmol, 2.1 eq.) and MN-
diisopropylethylamine (44.6 mL, 256 mmol, 2.1 eq.) in EtOH (150 mL) dropwise at 0 °C.
The reaction e is stirred overnight at room temperature and the solvent is removed
under reduced pressure. The crude product is extracted with dichloromethane (3 x 100
mL) and the organic phase is successively washed with saturated aqueous sodium
bisulfate (3 x 400 mL). The ed organic layers are dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The crude mixture is purified by
flash column chromatography (SiOz, cyclohexane / ethyl acetate 9:1 9 3:1) to yield i26
(5.02 g, 18%) and i2? (16.7 g, 59%), both as ess solids.
4-(4,6-dichloropyrimidinyl)morpholine (i26): 1H NMR (400 MHz, CDCI3): 8 6.56 (s, 1 H),
3.78 (m, 4 H) 3.74 (m, 4 H).
4-(2,6-dichloropyrimidinyl)morpholine (i27): 1H NMR (400 MHz, CDCI3): 8 6.41 (s, 1 H),
3.78 (m, 4 H), 3.65 (m, 4 H).
Method 11: S romor holino rimidin lmeth lmor holine i28
1’0”) 1”“
/§. + [0) ”b k?)
ab /‘ .. XN‘
£1 g);
Ci / N Cl )/ N N Ci
i27 I28
A solution of i27 (694 mg, 2.97 mmol, 1.0 eq.), (S)—3-methylmorpholine (0.500 mL,
4.46 mmol, 1.5 eq.) and N,N-diisopropylethylamine (1.29 mL, 7.43 mmol, 2.5 eq.) in EtOH
(5.0 mL) is heated to reflux for 3 days. Then, the solvent is removed under reduced
pressure. The residue is dissolved in dichloromethane (60 volumes) and washed with
saturated aqueous sodium bisulfate (3 x 60 volumes). The organic layer is dried over
anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude
mixture is ed by flash chromatography (SiOz, cyclohexane / ethyl acetate 3:1 9 1:1)
to afford the title compound (2-chloromorpholinopyrimidinyl)—3-
methylmorpholine (i28) as a colorless solid (425 mg, 48%). 1H NMR (400 MHz, CDCI3):
8 5.85 (s, 1 H), 4.62 (dd, 2.0,), = 13.6 Hz, 3.0,), = 2.9 Hz, 1 H), 4.25 (dd, 2.0,), = 13.6 Hz,
3.0,), = 2.9 Hz, 1 H), 3.93 (dd, 2.0,), = 11.4 Hz, 3.0,), = 3.8 Hz, 1 H), 3.75, (t, 3.0,), = 5.0 Hz,
4 H), 3.71 (s,1 H), 3.66 (dd, 2JH,H = 11.3 Hz, 3JH,H = 3.2 Hz,1 H), 3.53 (m, 5 H), 3.23 (m,
1 H), 1.26 (d, 2JH,H = 11.3 Hz, 3 H); MS (MALDI): m/z = 299.4 ([M+H]+).
Method 11 is also used for the preparation of the following intermediate compound i29.
Reagent Structure NMR M8
(O) 1H NMR (400 MHz, : MS WALD”: W2
93:. MN/ 85.86 (s, 1 H), 4.60 (brs, 2 H), =309-6([M+H1+)-
i29 {UN} 9/133] 3.80-3.72 (m,6H), 3.62-3.56 (m,
H (51’1“‘1011‘3N’E‘MC; 2H), 3.56-3.50 (m, 4H), 2.08-
0571 1.90 (m, 4 H).
Method 12: S romor holino rimidin lmeth lmor holine i30)
A solution of (S)—3-methylmorpholine (194 mg, 1.32 mmol, 1.5 eq.), i26 (300 mg,
1.28 mmol, 1.0 eq.) and N,N-diisopropylethylamine (3.0 eq.) in DMF (17 s) is
heated for 16 hours (130 °C). Then, the solvent is removed under reduced pressure. The
residue is ved in dichloromethane (100 volumes) and washed with saturated
aqueous sodium bisulfate (3 x 100 volumes). The organic layer is dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is
purified by flash chromatography (SiOz, cyclohexane/ethyl acetate 5:1) to afford the title
compound i30 as a colorless solid (257 mg, H NMR (400 MHz, CDCI3): 8 5.84 (s,
1 H), 4.18 (m, 1 H), 3.94 (m, 2 H), 3.71 (m, 10 H), 3.53, (dt, 2JHH = 12.0 Hz, 3JH,H = 3.1 Hz,
1 H), 3.20 (dt, 2.1.”, = 12.8 Hz, 3.1.”, = 3.8 Hz, 1 H), 1.27 (d, 3.1.”, = 6.8 Hz, 3 H); MS
(MALDI): m/z = 298.4 ([M]+).
Method 13: 4- 4-chloromor holino-1 3 5-triazin l mor holinone i31
E0] E21
NlN + [Cl ————» "lg”
i11 i31
A round bottom flask was charged with compound i11 (5.37 g, 22.9 mmol, 1.5 eq),
morpholine—3-one (1.54 g, 15.3 mmol, 1.0 eq), 4,5-bis(diphenylphosphino)—9,9-
dimethylxanthene (530 mg, 0.915 mmol, 0.06 eq.), cesium carbonate (9.95 g, 30.5 mmol,
2.0 eq) and palladium(ll) e (383 mg, 0.170 mmol, 0.04 eq.). The reaction mixture
was flushed with nitrogen and 1,4-dioxane (100 mL) was added. The reaction e was
stirred at reflux (100 °C) for 4 hours. The reaction mixture was cooled to room
temperature and filtered. The filter cake was washed with romethane (2x 30 mL).
ts were removed under reduced pressure and the crude product was purified using
silica gel chromatography (cyclohexane/ethyl acetate 1:0 9 1:3) to yield the title
compound i31 as a colorless solid (390 mg, 31%).1H NMR (400 MHz, CDCI3): 8 4.32 (s,
2 H), 4.03-3.97 (m, 4 H), 3.93-3.86 (m, 4 H), 3.75-3.73 (m, 4 H); MS (MALDI): m/z = 299.6
([M+Hl+)-
Method 14: 8— 4 loro-1 3 5-triazin l oxaazabic clo 3.2.1 octane i32
A solution of ic chloride (1.97 g, 10.7 mmol, 1.0 eq.) in dichloromethane (10 mL) is
cooled to — 50 °C. A solution of 3-oxaazabicyclo[3.2.1]octane hloride (1.60 g,
.7 mmol, 1.0 eq.) and N,N-diisopropylethylamine (3.73 mL, 21.4 mmol, 2.0 eq.) in
dichloromethane (40 mL) is slowly added over a period of 5 hours. The mixture is stirred
for another 5 hours at this temperature. Then, dichloromethane (20 mL) and saturated
aqueous sodium bisulfate (50 mL) are added and the mixture is allowed to warm to room
temperature. The layers are separated and the organic layer is washed with saturated
aqueous sodium bisulfate (2 x 50 mL). The organic layer is dried over anhydrous sodium
e and the solvent is removed under d pressure. The crude mixture is
recrystallized from n-heptane / dichloromethane (20 mL/ 13 mL) to afford the title
compound 8—(4,6-dichloro-1,3,5-triazinyl)oxaazabicyclo[3.2.1]octane (i32) as a
colorless solid (2.47 g, 47%). 1H NMR (400 MHz, CDCI3): 8 4.74 (m, 2 H), 3.72 (d,3JH,H =
1.5 Hz, 4 H), 2.08 (m, 4 H).
Method 14 is also used for the preparation of the following intermediate compounds i33
and i34.
Reagent Structure NMR
1H NMR (400 MHz, CDCI3): 5454-450 (m,
01 H), 4.20 (dd, 3J1”, = 2.9 Hz, 2J1”, = 14 Hz,
01. E k 1 H), 3.92 (dd, 3J1”, = 3.4 Hz, 2J1”, = 12 Hz,
i33 [hi/k ML 1 H), 3.71 (d, 2J1”, = 12 Hz, 1 H), 3.57 (dd,
H 3‘1 fi‘: 3J1”, = 3.2 Hz, 2J1”, = 12 Hz, 1 H), 3.42 (m,
0‘“ “N! Cl
1 H), 3.32 (m, 1 H), 1.27 (d, 3J1”, = 6.9 Hz,
3 H).
Lek ” 1H NMR (400 MHz, (CD3)ZSO): 5 3.88-
g" 111111 3.81 (m, 4 H), 3.51 (s, 2 H), 1.46 (s, 6 H).
J1 J1.
Cl N Ci
0 131.
1N” 4’01 19
f: g?
A f».
+ 11——> N 11
N‘ “N 1| ,1
”fl 11 :1 N MN ‘91
CE,«/ 1N." NC. f
offi? 1;)
i32 i35
To a solution of 3,7-dioxaazabicyclo[3.3.1]nonane (184 mg, 0.700 mmol, 1.0 eq.) and
N,N-diisopropylethylamine (0.170 mL, 0.970 mmol, 1.4 eq.) in 1,4-dioxane (1.0 mL) a
solution of i32 (100 mg, 0.770 mmol, 1.1 eq.) in 1,4-dioxane (2.0 mL) is added. The
resulting mixture is heated for1 hour at 70 °C. Then, dichloromethane (50 mL) and water
(50 mL) are added. The aqueous layer is extracted with dichloromethane (3 x 50 mL), the
combined organic layers are dried over anhydrous sodium sulfate and the solvent is
evaporated. The crude mixture is purified by automated flash tography on silica gel
(cyclohexane / ethyl acetate 2:1 9 0:1 ) to afford the title compound 9-(4-(3-oxa-8—
azabicyclo[3.2.1]octanyl)chloro-1 ,3,5-triazinyl)-3,7-dioxa
yclo[3.3.1]nonane (i35) as a colorless solid (192 mg, 77%).1H NMR (400 MHz,
SO): 8 4.70 (m, 1 H), 4.55 (m, 2 H), 4.44 (m, 1 H), 4.12 (m, 4 H), 3.90 (m, 4 H), 3.72
(m, 2 H), 3.64 (m, 2 H), 2.08 (m, 2 H), 1.97 (m, 2 H); MS (MALDI): m/z = 354.3 ([M]+).
Method 16: 9- 4-chloro R meth lmor holino -1 3 5-triazin l -3 7-dioxa-9—
azabicyclo|3.3.1|nonane (i36)
[ k L,CLL.
N"L 0 o
N M J‘; J
L + mgr/1,2 —> N” 1 N
NXQ‘LN \ / {fl /!
,1} 2.6L :1 N” “N “'01
‘‘‘‘‘‘
Cl“ ”‘N/ “Cl Off/:5?f
i33 i36
To a solution of 3,7-dioxa-9—azabicyclo[3.3.1]nonane (173 mg, 1.27 mmol, 1.05 eq.) and
N,N-diisopropylethylamine (0.50 mL, 2.52 mmol, 2.1 eq.) in tetrahydrofuran (5 mL) a
on of i33 (300 mg, 2.52 mmol, 2.1 eq.) in 1,4—dioxane (2.0 mL) is added. The
resulting mixture is heated for2 hours (70 °C). Then, ethyl acetate (20 mL) and saturated
aqueous sodium bisulfate (20 mL) are added. The phases are separated and the c
layer is washed with saturated aqueous sodium ate (2 x 20 mL). The organic layer is
dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure.
The crude mixture is purified by automated flash chromatography (Si02,
cyclohexane / ethyl e 2:1 9 0:1) to afford the title compound i36 as a colorless solid
(316 mg, H NMR (400 MHz, (CD3)ZSO): 8 4.55-4.53 (m, 1 H), 4.42 (m, 1 H), 4.32
(m, 1 H), 4.25-4.16 (m, 1 H), 4.01-3.97 (m, 4 H), 3.87 (dd, 3JH,H = 3.8 Hz, 2J1”, = 11.2 Hz,
1 H), 3.73-3.65 (m, 5 H), 3.53 (dd, 3.0,), = 3.0 Hz, 2.0,), = 11.6 Hz, 1 H), 3.38 (m, 1 H), 3.15
(m, 1 H), 1.20 (d, 3.0,), = 6.9 Hz, 3 H).
Method 16 is also used for the preparation of the following intermediate compounds i37 to
i53, and intermediate i82.
t Structure NMR MS
,,..o... 1H NMR (400 MHz,
.10... [KN/k (003)280): 6458-450 (m, MS (MALDI):
137 JWK Til/1%” 1H), 4.44—4.35 (m, 2H), m/z=328.2
H {wwaN/ACEl 4.25-4.12 (m, 1 H), 3.90- ([M+H]+).
ovk 3.86 (m, 1 H), 3.75—
3.65 (m, 3 H), 3.56-
3.49 (m, 3 H), 3.38 (m,
1 H), 3.16 (m, 1 H), 1.25 (d,
3.4,), = 6.9 Hz, 6 H), 1.19
(d, 3.4,), = 6.9 Hz, 3 H).
1H NMR (400 MHz,
80): 6 4.54-4.46 (m,
{XOXL 1 H), 4.18-4.13(m, 1 H),
.404, N 3.88 (m, 1 H), 3.80-
i38 {Wk {xi/EN 3.65 (m, 5 H), 3.54 (m,
H fixN/‘xmzixa 1H), 3.44-3.36 (m, 3H),
ow} 3.18 (m, 1 H), 1.44 (s, 6 H),
1.21 (d, 3.1%,), = 6.9 Hz,
3 H).
1H NMR (400 MHz,
(003)280): 64.65-451 (m,
XOR 2H), 4.31-4.20 (m, 2H),
,ok {NK 3.66 (m, 3 H), 3.69- MS (MALDI):
139 L “kyom 0». NAQN 3.56 (m, 2 H), 3.54- m/z= 344.2
fit {/]«.ij'\»N>:¢/i~~0; 3.48 (m, 3 H), 3.42— ([M+H]+).
06,} 3.35 (m, 2 H), 3.31 (s, 3 H),
3.21-3.13 (m, 2 H), 1.21 (d,
3.4,), = 6.9 Hz, 3 H).
1H NMR (400 MHz,
(003)280): 451 (m,
1H), 4.42-4.35 (m, 2H),
4.12-4.25 (m, 2 H), 4.04-
.29» E k 4.07 (m, 1 H), 3.86-
3.88 (m, 1 3.78-
m pg :f H),
W ‘f if 3.75 (m, 2 H), 3.69-3.65
H 1”qu \N “‘3“
(m, 1 H), 3.55-3.51 (m,
1H), 3.38 (m, 1H), 3.20-
3.13 (m, 1H), 2.68 (m,
1 H), 1.81 (m, 1 H), 1.20 (d,
3.4,), = 6.9 Hz, 3 H).
1H NMR (400 MHz,
(003)280): 8 4.69-4.53 (m,
”,0- 3H), 4.31-4.15(m, 1H),
#0 L k 3.93-3.78 (m, 3H), 3.71-
W“ ii 3.53 (m, 4 H), 3.42-
l41. N35;- 8N
H {:27”“1§””N’” “a: 3.16(m, 1H), 3.12-3.08
03% (m, 1H), 1.81 (m, 1H),
1.21 (d, 3.1),), = 6.9 Hz,
3 H).
1H NMR (400 MHz,
80): 8 4.95-4.88 (m,
1H), 4.64 (m, 1H),
.0. 4.54 (m, 1 H), 4.31-
,,GN [ML 4.09 (m, 1H,) 3.89-
MS ):
3.85 (m, 1 3.75-
_ .i H),
.42 m/z = 312.2
, ”fix-N
”N” 3.73 (m, 2 H), 3.66-3.63
,1 4, ([M+H]+)
H ((3)? 38’ “Ci '
(m, 2H), 3.52 (m, 1H),
O“ 1‘
3.45-3.32 (m, 3H), 3.18-
3.12(m, 1H), 1.90-
1.83 (m, 2 H), 1.21 (d, 3.1),),
= 6.9 Hz, 3 H).
1H NMR (400 MHz,
(003)280): 8 4.94-4.88 (m,
1H), 4.64 (m, 1H),
,0. 4.54 (m, 1 H), 4.29-
{ 3.89-
. 4.12(m, 1H), .»08 MS (MALDI): 4“..-
3.85 (m, 3.75-
I43_ m L 1H),
prN m/z=312.2
“1». ,9
N1 3.73 (m,
A 2H), 3.66-3.63
H /. ,
:- 1L
_, ([M+H] ).
(m, 2H), 3.52 (m, 1H),
3.45-3.32 (m, 2H), 3.18-
3.12 (m, 1 H), 1.90-
1.83 (m, 2 H), 1.21 (d, 3JH,H
= 6.9 Hz, 3 H).
1H NMR (400 MHz,
,,o.,\ (003)280): 84.82-4.17(m,
{LN/L 4 H), 3.88 (m, 1 H), MS (MALDI):
1': .
i44 12:7“ "3‘“ NAN 3.68 (m, 1 H), 3.54- m/z=326.8
F ::;T/rr-»,§¢»-3\~::«NLi901, 3 +
3.51 (m, 1 H), 3.41 (m, ([M+H] ).
F 1H), 3.25-3.15(m, 4H),
1.21 (m, 3 H).
1H NMR (400 MHz,
(003)280): 88.55-40 (m,
[f L 1 H), 4.65-4.77 (m, 1 H),
“N” MS (MALDI):
FL.../~ 4.36-4.01 (m, 3.83
_145 F“? NH2 A 3H),
m/z=312.1
f3 L L{V
(m, 1 H), 3.62 (m, 1 H),
1:, ).+
M g N c; 3.52 (m, 1 H), 3.35 (m,
1 H), 3.10 (m, 1 H), 1.18 (d,
, = 6.9 Hz, 3 H).
1H NMR (400 MHz,
(003)280): 8 8.12-7.89 (m,
1 H), 4.52 (m, 1 H),
4.16(m, 1 H), 3.88 (m,
MS (MALDI):
A N 1 H )
, 368
NHz A - (m, 1 H )
i46 WW ,
m/z=284.9
N” N 3.52 (m, 1 H), 3.35 (m, +
A, ,L. ji, ([M+H] )-
*T/ ii “N“ 0% 2H), 3.10(m,2H),1.18(d,
3.1),), = 6.9 Hz, 3 H),
1.04 (m, 1 H), 0.42 (m,
2 H), 0.20 (m, 2 H).
1H NMR (400 MHz,
(003)280): 85.10-497 (m,
f ]\ 2 H), 4.70-4.54 (m, 1 H),
F LN/ MS (MALDI):
L H 4.25 (m, 1 3.91
_147 92L L H), (m,
4;. m/z=313.6
g: :31 1 H), 3.71 (m, 1 H), +
8. m A» A L ([M+H1).
F4 0 N 0* 3.57 (m, 1 H), 3.41 (m,
1 H), 3.29 (m, 1 H), 1.25 (d,
3.1),), = 6.9 Hz, 3 H).
1H NMR (400 MHz,
(003)280): 66.37 (m, 1 H),
,0»,
1 4.68-4.53 (m, 3 H),
MS (MALDI):
P W N1\
7 4 25 (m 1 H) 3 90 (m
‘3” ,«L ' ’ ’ ' ’
M8 m/z= 295.7
1:: ;f 1 H), 3.70 (m, 1 H),
6:, A x, / ([M+H], )-
2; 0 N C' 3.55 (m, 1 H), 3.41 (m,
1 H), 3.25 (m, 1 H), 1.24 (d,
3JH,H = 6.9 Hz, 3 H).
1H NMR (400 MHz,
3.0,, (003)280): 64.55 (m, 1 H),
l, L 4.21 (m, 1H), 3.89 (m,
1:} N MS (MALDI):
WW»). 3.79-3.66 (m,
_ 3L, 1H), 5H),
:49 or I NH N“ N m/z= 326.2
waw H 3.54-3.51 (m,
, l, fl 3H), 3.45-
g 35”” N N (33 ([M+H] ).
a; :,.,l 3.32 (m, 3 H), 3.11 (m,
.1, ”H 1 H), 2.97 (m, 2 H), 1.20 (d,
3JH,H = 6.9 Hz, 3 H).
1H NMR (400 MHz,
.0, (003)280): 64.56 (m, 1 H),
E L 4.24 (m, 3 H), 3.88 (m,
H N MS (MALDI):
‘1’ ‘1 "3 l 1H), 3.77 (m, 2H), 3.67-
150_ [ I NH N“ N m/z= 342.8
6 H 4. ,l, fl 3.51 (m, 8 H), 3.40-3.37
g Q,1, N‘ N c: ([M+H], ).
1W; (m, 1 H), 3.16 (m, 1 H),
1 A,
‘1—0’ “H 1.21 (d, 3JH,H = 6.9 Hz,
3 H).
1H NMR (400 MHz,
,0, (003)280): 64.56 (m, 1 H),
H LNL 4.24 (m, 1 H), 3.87 (m,
H), 3.68 (m, 1
_ H),
151 N“ N
a, 1
A, 1,, 1,1, 3.53 (m, H), 3.35 (m,
/‘- 1” “‘N/ “N“ “C:
F F
F if 1 H), 3.18 (m, 1 H),
:3 2.01 (m, 4 H), 1.21 (d, 3JH,H
= 6.9 Hz, 3 H).
1H NMR (400 MHz,
(003)280): 6 4.53 (m, 1 H),
{/01 4.35 (m, 5 H), 4.20 (m,
1 H), 3.87 (m, 1 H), MS (MALDI):
i52 L, J NVEN 3.65 (m, 4 H), 3.52 (m, m/z=340.2
;; ”1:: [1“‘“*N~“”L“N“"cs 1 H), 3.37 (m, 1 H), ([M+H]+).
gm""" 3.16 (m, 1 H), 1.79 (m,
4 H), 1.20 (d, 3.1),), =
6.9 Hz, 3 H).
1H NMR (400 MHz,
(003)280): 64.65 (m, 1 H),
4.55 (m, 1 H), 4.32 (m,
LN/L 1H), 4.22(m, 2H),
H MSWALDD:
,9 N 3.98 (m 1 H
, ) , 3.86 (m,
i53 HO \{ ”1g HO“, 5k m/z = 330.1
,5, ,5 1 1. 2 H), 3.63 (m, 2 H),
6 ,
(3f 3N”/
"C‘ ([M+H] )-
3.55 (m, 1 H), 3.49-
3.34 (m, 4 H), 3.17(m,
1 H), 3.12 (m, 1 H), 1.21 (d,
3.1),), = 6.9 Hz, 3 H).
1H NMR (400 MHz,
80): 6 4.67-4.53 (m,
1H), .34 (m, 2H),
112:3:(,0.3 4.31-4.09
, (1m, 1H,
MSWALDD:
3.88 (m, H), 3.68 (m),
i82 WOT
N m/z = 328.3
. A
H fi/“N’W‘N‘f c; 1 H), 3.55 (m, 3 H),
o. ,3 ([IVI+H] + )-
3.38 (m, 1 H), 3.13 (m,
1 H), 2.55 (m, 2 H), 1.20 (d,
3.1),), = 6.9 Hz, 3 H), 1.19
(d, 3.1),), = 6.9 Hz, 6 H).
WO 75130
Method 17: 9- 4-chloro 3 3-dimeth lmor holino -1 3 5-triazin l -3 7-dioxa-9—
azabicyclo|3.3.1|nonane (i54)
“NM M
z? 1%,? 4
m H m
i34 i54
To a solution of 3,7-dioxa-9—azabicyclo[3.3.1]nonane (155 mg, 1.20 mmol, 1.05 eq.) and
N,N-diisopropylethylamine (0.42 mL, 2.40 mmol, 2.1 eq.) in 1,4-dioxane (5 mL) a solution
of i34 (300 mg, 1.14 mmol, 1 eq.) in 1,4-dioxane (1 mL) is added. The resulting mixture is
heated for 2 hours (70 °C). Then, ethyl acetate (20 mL) and saturated aqueous sodium
bisulfate (20 mL) are added. The phases are separated and the organic layer is washed
with saturated aqueous sodium bisulfate (2 x 20 mL). The organic layer is dried over
anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude
e is purified by automated flash chromatography (8102, cyclohexane / ethyl acetate
2:1 9 0:1) to afford the title nd i54 as a colorless solid (178 mg, 44%). 1H NMR
(400 MHz, (CD3)ZSO): 8 4.32 (m, 2 H), .98 (m, 4 H), 3.77 (m, 4 H), 3.71 (m, 4 H),
3.44 (m, 2 H), 1.41 (s, 6 H). MS (MALDI): m/z = 356.3 ([M+H]+).
Method 17 is also used for the preparation of the following intermediate compounds i55 to
i64.
t Structure NMR MS
1H NMR (400 MHz,
(003)280): 5 4.36 (m,
3.77—3.74 (m, MS (MALDI):
. ,o.
” LN? 2H),
I55 JaNk NAN 6H), 3.55 (m, 2H), m/z=343.0
H (AN/isN/Lml %
3.44 (m, 2 H), 1.44 (s, ([M+H] ).
0wk 6 H), 1.26 (d,
3.1),), = 6.9 Hz, 6 H).
1H NMR (400 MHz,
(003)280): 8452 (m,
1 H), 4.20 (m, 1 H),
3.90 (m, 2 H), 3.77 (m,
i56 [ -]\/0-. 4 H), 3.65 (m, 1 H),
3.51-3.41 (m, 5 H),
3.28 (s, 3 H), 3.12 (m,
1 H), 1.44 (s, 3 H),
1.43 (s, 3 H).
1H NMR (400 MHz,
(CD3)280): 84.98 (m,
1 H), 4.35 (m, 1 H),
4.18 (m, 1 H), 4.00 (m,
MS (MALDI):
1 3.87 (m, 1
i57 W'fi’: H), H),
J m/z = 344.2
3.81-3.65 (m, 5 H),
([M+H]+)-
3.51-3.35 (m, 5 H),
3.21-3.04 (m, 1 H),
1.44 (s, 3 H), 1.45 (s,
3 H).
1H NMR (400 MHz,
(CD3)280): 8 3.77 (m,
4 H), 3.65 (m, 4 H), MS (MALDI):
i58 {4. j 3.44 (m, 2 H), 2.56 (m, m/z = 351.2
4 H), 1.64 (m, 1 H), ([M+H]+)-
1.44 (s, 6 H), 0.44 (m,
2 H), 0.35 (m, 2 H).
1H NMR (400 MHz,
(CD3)280): 8 3.76 (m,
4 H), 3.68 (m, 4 H), MS (MALDI):
159 ”N .44 (m, 4 H), m/z = 369.0
3.24 (m, 3 H), 2.52- ([M+H]+)-
2.45 (m, 6 H), 1.44 (s,
6 H).
W0 2016/075130 2015/076192
1H NMR (400 MHz,
((303)280): 65.56 (m,
0 [01:5 MS (MALDI):
. 1 4.87 (m, 2 H),
mo Q\ T H),
m/z=3o1.1
09: 4.60 (m, 2 H), 3.81 (m,
Q If? ([M+H]+).
6” «CNN/1 4 H), 3.48 (m, 2 H),
3.13 (s, 6 H).
1H NMR (400 MHz,
,0 (CD3)2SO): 65.46 (m,
0.: I: M 1 H), 3.84-3.73 (m, MS (MALDI):
"51 J: 3: 8H), 3.49 (m, 2H), m/z=315.0
4: l i]: E]: 2.21 (m, 1 H), 2.05 (m, ([M+H]+).
0" MN: 0* 1 H), 1.46 (s, 3 H).
1.45 (s, 3 H).
1H NMR (400 MHz,
(003)280): 65.46 (m,
0.,“ L if 1 H), 3.84-3.73 (m, MS (MALDI):
{W5 :E :
"52 8H), 3.49 (m, 2H), m/z=315.0
0“ f: I]: E] 2.21 (m, 1 H), 2.05 (m, ([M+H]+).
O: N: C‘
1 H), 1.46 (s, 3 H).
1.45 (s, 3 H).
1H NMR (400 MHz,
LOL (003)280): 85.11 (m,
MS (MALDI):
1 3'82 (m’ 6 H)’
i63 E} E H)’
m/z= 329.8
9»bu ’“ ff:
o l 84%; 3.47 (m, 4 H), 1.99 (m,
.15. ,1 ).
”5‘“ “0’ N” ““01 2H), 1.65 (m, 2H),
1.46 (s, 6 H).
0 1H NMR (400 MHz,
(«'me Egg/"L” (003)280): 84.12 (m, MS (MALDI):
i64 0653:“) 4 H), 3.79 (m, 4 H), m/z= 362.9
.. WEE
0 “Ci 3.46 (m, 2 H), 3.22 (m, ([M+H]+).
0:81 If N
6’ E5"
4 H), 1.46 (s, 6 H).
Method 18: 4-(difluoromethyl)gyridin-Z-amine (i65)
F F F F
\ \
I W, l
/ /
N Cl N NH2
Palladium acetate (275 mg, 1.22 mmol, 0.05 eq.) and 2-dicyclohexylphosphino—2’,4’,6’-
triisopropylbiphenyl (Sigma-Aldrich, product number 638064, 1.17 g, 2.45 mmol, 0.10 eq.)
are dissolved in 1,4-dioxane (10 mL) under nitrogen atmosphere, and the resulting
mixture is allowed to stir at room temperature for 45 minutes. This on is then added
to a mixture of tert—butylcarbamate (Sigma, product number 167398, 4.30 g, 36.7 mmol,
1.5 eq.), Cs2C03 (15.9 g, 48.8 mmol, 2.0 eq.) and 2-chlorodifluoromethyl-pyridine
(Manchester cs, product number , 4.00 g, 24.5 mmol, 1.0 eq.) in 1,4-
dioxane (80 mL) under nitrogen atmosphere. The resulting reaction e is then heated
at 90 °C for 3 hours, during which it turned brownish. After this time, the e is allowed
to cool to room temperature. It is then diluted with ethyl acetate, washed with an aqueous
saturated solution of ammonium chloride (2 x 30 mL) and deionized water. The c
layer is dried over anhydrous sodium sulfate, filtered and the t is evaporated under
reduced pressure. The brownish residue is mixed with 4 M HCI in dioxane (50 mL,
) and methanol (20 mL), and then heated at 80 °C for 45 s. Deionized water
is added and the aqueous layer is washed with ethyl acetate (3 x). The aqueous layer is
then basified to pH = 9, with solid sodium hydroxide. The aqueous layer is extracted with
ethyl acetate (3 x). The combined organic layer is dried over anhydrous sodium sulfate,
filtered and concentrated to dryness under reduced pressure. The desired product i65 is
obtained as a colorless solid, which is used in the next step without further purification
(98% yield). 1H NMR (400 MHz, CDCI3): 8 8.16 (d, 2JH), = 5.2 Hz, 1 H), 6.74 (d,
2JH), = 4.8 Hz, 1 H), 6.59 (s, 1 H), 6.51 (t, 2JHf = 56 Hz, 1 H), 4.61 (br s, 2 H);
19F NMR (376 MHz, 00013): 5 — 116.0 (s, 2 F).
Method 19: 5-bromo difluorometh l ridinamine i66
F F F F
\ \
l " l
/ /
N NH2 N NH2
i65 I66
2015/076192
To a solution of compound i65 (3.00 g, 20.8 mmol, 1.0 eq.) in tetrahydrofuran (60 mL) is
added N-bromosuccinimide (3.89 g, 21.9 mmol, 1.05 eq.) at 0 °C in an ice bath. The
resulting mixture is stirred overnight, while it is allowed to warm up to room temperature.
Ethyl acetate is added and the organic layer is washed with aqueous sodium ate
(8%). The organic layer is then separated and acidified with an aqueous 3 M HCl-solution.
The s layer is washed with ethyl acetate (3 x 50 mL) and then basified to pH = 10,
with solid sodium hydroxide. The aqueous layer is extracted with ethyl acetate
(3 x 50 mL). The combined organic layer is dried over ous sodium sulfate, filtered
and concentrated to dryness under reduced pressure. The desired product i66 is obtained
as a sh solid, which is used in the next step without further purification (79% yield).
1H NMR (400 MHz, CDCI3): 6 8.20 (s, 1 H), 6.75 (s, 1 H), 6.71 (t, 2J7); = 54 Hz, 1 H);
4.62 (br s, 2 H); 19F NMR (376 MHz, 00013): 6 — 118.9 (s, 2 F).
Method 20: N’- 5-bromo difluorometh l ridin l -N N-dimeth midamide i67
F F F F
Br Br
\ \
E I
N/ N/ NArx'i// NH2
i66 i67
To a solution of compound i66 (3.68 g, 16.5 mmol, 1.0 eq.) in tetrahydrofuran (50 mL) is
added N,N-dimethylformamide dimethyl acetal (Manchester Organics, t number
005030, 3.30 mL, 24.8 mmol, 1.5 eq.) and the resulting mixture is stirred at 60 °C for
3 hours. The mixture is d to cool to room temperature and the solvent is evaporated
under reduced pressure. The crude product is purified by column tography on
silica gel (cyclohexane / ethyl acetate 1:1) to afford the desired product i67 as a yellowish
solid (82% yield). 1H NMR (400 MHz, CDCI3): 8 8.43 (s, 1 H), 8.34 (br s, 1 H), 7.17 (s,
1 H), 6.73 (t, ZJHf = 54 Hz, 1 H), 3.12 (s, 3 H), 3.10 (s, 3 H); 19F NMR (376 MHz, 00013):
8 — 118.6 (s, 2 F); MS (MALDI): m/z = 278.5 ([M+H]+).
Method 21: N’- 4- difluorometh l 4 4 5 5-tetrameth H 3 2-dioxaborolan l ridin
yl)—N,N-dimethylformimidamide (i68)
F F QC? F F
\ O’B \
I ‘
N/ NAT/ N/ NAT/
i67 i68
To a 2 M on of pylmagnesium chloride (Sigma, product number 230111,
3.10 mL, 6.20 mmol, 1.15 eq.) in tetrahydrofuran (6 mL) is slowly added a solution of
compound i67 (1.50 g, 5.39 mmol, 1.0 eq.) in tetrahydrofuran (5 mL) at 0 °C. The resulting
brownish mixture is stirred at 0 °C for 45 minutes and then at room temperature for
s. After this time, TLC ring hexane / ethyl acetate 1:1) showed
complete consumption of starting material. 2-lsopropoxy—4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (Manchester Organics, product number W23343, 1.43 mL, 7.00 mmol,
1.3 eq.) is added and the mixture is heated at 60 °C for 3 hours. The mixture is then
placed in an Erlenmeyer flask, cooled to 0 °C with an ice bath and quenched with a 15%
aqueous solution of ammonium chloride. The layers are separated and the aqueous layer
is extracted with ethyl acetate (3 x 40 mL). The combined organic layers are dried over
anhydrous sodium sulfate, filtered and the t is evaporated under reduced pressure.
Heptane is added and the organic layer is washed with a saturated aqueous on of
sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and then concentrated
to dryness under reduced pressure. The desired product i68 is obtained as a brownish oil,
which is used in the next step t further purification (94% yield). 1H NMR (400 MHz,
CDCI3): 8 8.66 (s, 1 H), 8.51 (s, 1 H), 7.34-7.04 (m, 2 H), 3.12 (s, 3 H), 3.12 (s, 3 H),
1.34 (s, 12 H); 19F NMR (376 MHz, CDCI3): 8 — 115.6 (s, 2 F); MS ):
m/z = 326.0 ([M+H]+).
Method 22: 4- difluorometh l rimidinamine i69
F F
o o
FVLOJYF m. N
F F NH2
To a solution of ethyl vinyl ether (4.00 mL, 41.8 mmol, 1.0 eq.) in a mixture of
pyridine (4.10 mL, 50.7 mmol, 1.2 eq.) and dichloromethane (40 mL), is added dropwise a
solution of 2,2-difluoroacetic anhydride (Manchester Organics, (product number L24754,
.90 mL, 50.1 mmol, 1.2 eq.) in dichloromethane (5 mL) at - 70 °C in a dry ice/
isopropanol bath. The ing solution is allowed to warm up to room ature
overnight. The mixture is then washed with zed water, dried over anhydrous sodium
sulfate, filtered and the t is evaporated under reduced pressure to afford an orange
A on of guanidine-HCI (Sigma, product number 50940, 4.80 g, 50.2 mmol, 1.2 eq.) in
ethanol (20 mL) is stirred at room temperature for 1 hour. To this solution are added
sodium hydroxide pellets (2.00 g, 50.0 mmol, 1.2 eq.) in one portion. The resulting
suspension is stirred at room temperature overnight.
The resulting mixture is diluted with dichloromethane (20 mL) and added dropwise over
1 hour. The resulting suspension is stirred at room ature for 2 hours.
Dichloromethane is evaporated under reduced pressure. Deionized water (25 mL) is
added to the residue. The resulting mixture is stirred vigorously for 2 hours and is then
allowed to stand at room temperature overnight. The formed solid is filtered off, washed
with deionized water (2 x) and heptane (1 x) and then dried in vacuo. The desired product
i69 is obtained as a colorless solid (65% yield). 1H NMR (400 MHz, : 8 8.43 (d,
2.0,), = 4.8 Hz, 1 H), 7.02 (br s, 2 H), 6.76 (d, 2.0,), = 5.2 Hz, 1 H), 6.67 (t, ZJHf = 55 Hz,
1 H); 19F NMR (376 MHz, 00013): 8 — 120.5 (s, 2 F).
Method 23:-b--romo4 difluorometh l rimidinamine i70
F F
NANHZ
i69 i70
To a solution of compound i69 (3.00 g, 20.7 mmol, 1.0 eq.) in tetrahydrofuran (90 mL) is
added N-bromosuccinimide (3.86 g, 21.7 mmol, 1.0 eq.) portionwise at 0 °C. The reaction
mixture is allowed to warm up to room temperature overnight. After this time, the solvent
is evaporated under reduced pressure. The residue is taken up in ethyl e (200 mL),
washed with an aqueous saturated solution of sodium carbonate (4 x), dried over
anhydrous sodium sulfate, filtered and then concentrated to dryness under reduced
pressure. The d product i70 is obtained as a yellowish solid, which is used in the
next step without further purification (98% yield). 1H NMR (400 MHZ, (CD3)ZSO): 8 8.50 (s,
1 H), 7.30 (br s, 2 H), 6.87 (t, ZJHf = 53 Hz, 1 H); 19F NMR (376 MHz, (CD3)ZSO):8 — 121.4
(s, 2 F).
Method 24: N-tert—but l carbox late-N- 5-bromo difluorometh l rimidin l -
a—(_)crbamatei71
BjfiiNNH2 —. F F
NANBocz
i70 i71
Compound i70 (4.35 g, 19.4 mmol, 1.0 eq.) and 4-(dimethylamino)pyridine (480 mg,
3.92 mmol, 0.20 eq.) are dissolved in tetrahydrofuran (50 mL). N,N-Diisopropylethyl-
amine (7.50 mL, 42.1 mmol, 2.2 eq.) and di-terf—butyl dicarbonate (9.33 g, 42.7 mmol,
2.2 eq.) are then added at 0 °C and the resulting solution is d to warm up to room
temperature overnight. The solvent is evaporated under reduced pressure. The crude
product is purified by column chromatography on silica gel (cyclohexane / ethyl acetate
9:1 —> 4:1 ) to afford the d product i71 as a colorless solid (85% .
1H NMR (400 MHz, CDCI3): 8 8.92 (s, 1 H), 6.73 (t, 2J1); = 53 Hz, 1 H), 1.47 (s, 18 H);
19F NMR (376 MHz, 00013): 5 — 120.4 (s, 2 F).
Method 25: methyl (4R,5R)—5-methyloxo-oxazolidinecarboxylate (i72)
o f o, /
[mo JO
H293” :M
‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘W, H131 :1”
Ho «<27 0’
Under en atmosphere, an oven-dried flask equipped with a reflux condenser is
charged with H-D-allo—threonine methyl ester-HCI (Bachem, product number 4044567,
2.00 g, 11.8 mmol, 1.0 eq.) and triphosgene (1.16 g, 3.91 mmol, 0.33 eq.).
Tetrahydrofuran (20 mL) is added and the resulting e is heated to reflux for 1 hour.
The mixture is then cooled down to room temperature, an aqueous NH4CI-solution (15%)
is added and the aqueous layer is extracted with dichloromethane (3 x). The combined
organic layer is dried over anhydrous sodium sulfate, ed and the solvent is
evaporated under reduced pressure. Purification by column chromatography on silica gel
(cyclohexane / ethyl e 1:1) gives the desired intermediate i72 as a colorless oil
(66% yield). 1H NMR (400 MHz, (CD3)ZSO): 8 7.98 (br s, 1 H), 4.91-4.82 (m, 1 H), 4.42 (d,
3.1.”, = 8.4 Hz,1 H), 3.71 (s, 3 H), 1.17 (d, 3.1.”, = 6.5 Hz, 3 H).
WO 75130
Method 26: 4S 5R tert—but Idimeth lsil lox meth lmeth l-oxazolidinone
(i73)
o. f“
yo [Morse
HNL’" “a“... . Hr?” “:f
:34 ”‘0 o’ifiW‘O
i72 I73
To a solution of methyl (4R,5R)—5-methyloxo-oxazolidinecarboxylate (i72, 1.18 g,
7.41 mmol, 1.0 eq.) in tetrathydrofuran (15 mL) is added LiBH4 (200 mg, 9.18 mmol,
1.2 eq.) portionwise at 0 °C under nitrogen atmosphere. The reaction e is allowed to
stir at 0 °C for 10 minutes and then at room temperature for 1.5 hours. The on
mixture is ed by addition of an aqueous saturated Nl-l4CI-solution, stirred for an
onal hour at room temperature and then reduced to dryness under d
pressure. The resulting residue is triturated with a mixture of ethyl acetate and
dichloromethane (1:1), the solids are filtered off, washed with ethyl
acetate / dichloromethane (1:1) and the filtrate is reduced to dryness under reduced
pressure. The above residue is then dissolved in N,N-dimethylformamide (20 mL).
lmidazole (581 mg, 8.53 mmol, 1.2 eq.) and tert—butyldimethylsilyl chloride (1.23 g,
8.16 mmol, 1.1 eq.) are added and the resulting reaction mixture is stirred at room
temperature overnight. Brine is added and the aqueous layer is ted with ethyl
acetate (3 x). The combined organic layer is dried over anhydrous sodium sulfate, filtered
and the t is evaporated. Purification by column chromatography on silica gel
(cyclohexane / ethyl acetate 3:1) gives the desired intermediate i73 as a colorless solid
(64% yield). 1H NMR (400 MHz, (CD3)ZSO): 8 7.41 (br s, 1 H), 4.72-4.63 (m, 1 H), 3.66-
3.61 (m, 1 H), 3.58 (br d, 3.0,), = 4.4 Hz, 2 H), 1.32 (d, 3.0,), = 6.6 Hz, 3 H), 0.86 (s, 9 H),
0.05 (d, UH), = 2.6 Hz, 6 H).
General procedure 1:
R2 “ F... F if
l\ ”O
x/ 3% 2F“ F
X“: x2 N .38.. ,/ X; X
l ,J, O m:
'3' 1 —p é‘i‘N 3”1
R “x. /“-«.
RV X3/NCS T X
“NW [N Ti 1
m. ,4 a
ll N Nil—£2
i68 (I)
Substituted monochloro-triazine or substituted monochloro—pyrimidine (1.0 eq.),
compound i68 (1.1 eq.), potassium phosphate tribasic (2.0 eq.) and chloro(2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl) [2-(2’-amino-1,1’-biphenyl)]-palladium(|l)
(Sigma-Aldrich, product number 741825, 0.05 eq.) are charged in a flask. Under nitrogen
atmosphere, 1,4-dioxane (30 s) and deionized water (1.5 volume) are added and
the ing mixture is then directly placed into an oil bath pre-heated at 95 °C. The
reaction mixture is stirred at this temperature for 2 hours. A 5 M s HCI-
solution (20 eq.) is added. The resulting mixture is heated to 60 °C ght. The pH of
the resulting e is ed to 8-9 by addition of a 2 M aqueous solution of sodium
hydroxide, the mixture is then extracted with ethyl acetate (3 x 20 volumes). The
combined organic layers are dried over anhydrous sodium sulfate, filtered and the solvent
is evaporated under reduced re. Purification by flash chromatography affords the
desired products of structure (I).
General procedure 2:
l R2
F3- F» ,F R2 k F
- ’,F X1 «x X2F\
\ f“’0 l 3 13
B. l é xx? t L. /
13/ \N O I; 5N 3 + NN 61‘ R1 X3 RN
2L- {/L- —>
g R‘ x3 ‘C: R N ,1-
N‘ N(Boc)2 N N(Boc)2 3 N NH2
i71 (I)
Compound i71 (1.0 eq.), 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(Manchester Organics, product number M23170, 1.5 eq.), potassium acetate (3.0 eq.) and
[1,1’-bis(diphenylphosphino)—ferrocene]—dichloropalladium(ll) (Sigma-Aldrich, product
number 697230, 0.099 eq.) are dissolved in 1,4-dioxane (12.5 s) under nitrogen
atmosphere. The resulting mixture is heated at 100 °C for 15 minutes (solution turned
black). TLC monitoring (cyclohexane / ethyl acetate 3:1) is used to show complete
consumption of starting al.
To the resulting e, substituted chloro-triazine or substituted chloro-
pyrimidine (1.1 eq.), an s solution of potassium carbonate (2 M, 3.0 eq.) and a
previously mixed solution of triphenylphosphine (0.12 eq.) and palladium
acetate (0.04 eq.) in tetrahydrofuran (100 volumes) are added. The resulting mixture is
heated at 60 °C for 2 hours and subsequently allowed to cool to room ature.
A 5 M aqueous HCl-solution (20 eq.) is added. The resulting mixture is heated to 60 °C
overnight. The pH of the resulting mixture is adjusted to 8-9 by addition of a 2 M aqueous
solution of sodium hydroxide, the mixture is then extracted with ethyl acetate (3 x 20
volumes). The combined organic layers are dried over anhydrous sodium sulfate, filtered
and the solvent is ated under reduced pressure. Purification by flash
chromatography affords the desired products.
Method 27: tert—but | N-tert—butox carbon l-N- 5- 4-chloromor holino-1 3 5-triazin
l difluorometh | rimidin mate i74
[,0 \ ,.o\_
I N :N]
F [F\ ,F
/“Qs
1 A, F F 35
“\ ,é, “N N
x o /\ "l
'3‘ 1: k I
E N ~~N
,_ TI ’ / A“ /l
L at C: "N” c: N N U
“N“ ‘N(soc)2 lg V N "N(Boc)2
(800)2N N
i71 i11 i74
Intermediate i71 (2.00 g, 4.71 mmol, 1.0 eq.), bis(pinacolato)diboron (1.80 g, 7.09 mmol,
1.5 eq.), KOAc (1.60 g, 16.3 mmol, 3.4 eq.) and [1 ,1’-bis(diphenylphosphino)ferrocene]-
dichloropalladium(ll) (350 mg, 478 umol, 0.10 eq.) are mixed in 1,4-dioxane under
en atmosphere and heated at 95 °C for 45 minutes. A pre-catalyst solution of
palladium(||) e (43.0 mg, 192 umol, 0.04 eq.) and triphenylphosphine 148 mg,
564 umol, 0.12 eq.) in tetrahydrofuran (2 mL) is also prepared and d at room
temperature for 1 hour. This solution is then added to the cooled above solution at room
temperature, followed by the addition of 4-(4,6-dichloro-1 ,3,5-triazinyl)morpholine i11
(1.65 g, 7.05 mmol, 1.5 eq.) and s K2C03-solution (2.4 M, 5.90 mL, 14.2 mmol,
3.0 eq.). The resulting mixture is heated at 55 °C overnight. After this time, the mixture is
poured onto an s NH4CI-solution (15%) and extracted with ethyl e (3 x). The
combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated
under d pressure. Purification by column chromatography on silica gel
(cyclohexane / ethyl acetate 1:0 9 4:1) gives product i74 as a colorless solid (36% yield).
1H NMR (400 MHz, CDCI3): 8 9.57 (s, 1 H), 7.55 (t, 2J7); = 54 Hz, 1 H), 3.99-3.91 (m, 4 H),
3.84-3.76 (m, 4 H), 1.49 (s, 18 H); 19F NMR (376 MHz, CDCI3): 8 — 121.0 (s, 2 F).
Method 28: 2R 3S amino tert—but ldi hen lsil lox butanol i75
1 46
”fl/LNTWWNCH {ii‘i
—> ““““““ \YXWOTEDPS
it} H2 {QH2
D-allo—Threoninol (307 mg, 2.92 mmol, 1.0 eq.) is dissolved in N,N-dimethylformamide
(3 mL) and imidazole (597 mg, 8.77 mmol, 3.0 eq.) is added. After 5 minutes, TBDPSCI
(760 uL, 2.92 mmol, 1.0 eq.) is added slowly and then the reaction mixture is stirred at
room temperature overnight. After this time, the solvent is evaporated under reduced
pressure. The resulting e is taken up in ethyl acetate and washed with an aqueous
saturated on of sodium bicarbonate (1 x) and brine (1 x). The organic layer is dried
over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
Purification by column chromatography on silica gel (100% ethyl acetate) gives the
desired intermediate i75 as a colorless lid (50% yield). 1H NMR (400 MHz, CDCI3):
8 7.70-7.61 (m, 4 H), 7.47-7.36 (m, 6 H), 3.82-3.73 (m, 1 H), 3.69 (d, 3JH,H = 5.8 Hz, 2 H),
2.58 (q, 3.1.”, = 5.8 Hz,1 H), 1.12 (d, 3.1.”, = 6.5 Hz, 3 H), 1.07 (s, 9 H).
Method 29: 4S 5R tert—but ldi hen lsil lox meth l 5-meth loxazolidinone i76
w—OTBDPS
.1... HM“7
xx Wm,
xi. OTEDPS N...............................g. XEL /M
f‘jfiig OJ" 0
i75 i76
Under nitrogen atmosphere, in an oven-dried flask equipped with a reflux condenser,
intermediate i75 (433 mg, 1.26 mmol, 1.0 eq.) and triethylamine (440 uL, 3.15 mmol,
2.5 eq.) are dissolved in romethane (5 mL). At 0 °C in an th, triphosgene is
then added (187 mg, 630 umol, 0.5 eq.). The resulting mixture is stirred overnight, while it
is d to warm up to room temperature. The reaction is then quenched by addition of
an aqueous NH4CI-solution (15%) and the aqueous mixture is extracted with
dichloromethane (3 x). The combined organic layer is dried over anhydrous sodium
sulfate, ed and the t is evaporated under reduced pressure. Purification by
column chromatography on silica gel (cyclohexane/ ethyl acetate 1:0 9 3:2) gives the
desired intermediate i76 as a colorless solid (73% yield). 1H NMR (400 MHz, CDCI3):
8 7.66-7.61 (m, 4 H), 7.47-7.38 (m, 6 H), 4.99 (brs, 1 H), .74 (m, 1 H), 3.85-
3.79 (m, 1 H), 3.68-3.65 (m, 2 H), 1.34 (d, 3JH,H = 6.7 Hz, 3 H), 1.06 (s, 9 H).
Method 30: 4S 5R tert—but ldi hen lsil lox meth l 3dibromo rimidin l-
-methyloxazolidin-2—one (i7?)
WOTBDPS 3’
NWN H111] , :5
N N -oraops
”fimVA + m»
Br Br 2L >a ”igwéjm’
0 Br N [‘
0’ 1 M
1*?”5‘0
i76 i77
Under nitrogen atmosphere, (4S,5R)—4-(((tert—butyldiphenylsilyl)oxy)methyl)—5-
methyloxazolidin-2—one (i76, 681 mg, 1.84 mmol, 1.0 eq.) is dissolved in N,N-
dimethylformamide (10 mL) and NaH (60% dispersion in mineral oil, 155 mg, 3.88 mmol,
2.1 eq.) is added portionwise at 0 °C, in an ice-bath. After 5 minutes, 2,4,6-
mopyrimidine (583 mg, 1.84 mmol, 1.0 eq.) is added. The resulting mixture is stirred
overnight, while it is allowed to warm up to room temperature. The on is then
quenched by addition of an aqueous NH4CI-solution (15%) and the aqueous mixture is
extracted with ethyl acetate (3 x). The combined organic layer is dried over anhydrous
sodium sulfate, filtered and the solvent is evaporated under reduced pressure. Purification
by column tography on silica gel (cyclohexane / ethyl e 1:0 9 9:1) gives the
desired product i77 as a colorless foam (55% . 1H NMR (400 MHz, CDCI3): 8 8.25 (s,
1 H), 7.54-7.50 (m, 2 H), 7.45-7.33 (m, 6 H), 7.26-7.21 (m, 2 H), 4.85 (quint,
3.1.”, = 6.9 Hz, 1 H), .52 (m, 1 H), 4.14 (dd, 2.1.”, = 12 Hz, 3.1.”, = 2.8 Hz, 1 H),
3.98 (dd, 2.1.”, = 12 Hz, 3.1.”, = 1.4 Hz, 1 H), 1.77 (d, 3.1.”, = 6.5 Hz, 3 H), 1.04 (s, 9 H).
[04.
f l
l j
.\ .0. if
N *N «creeps N 5N «OTBDPS
3 i ( + T j m
“N. f‘ E: /2\
Br / hil/ .M {31! 8:“ V“ ‘65” x...
./ /
(ff/“- 0’ (Sf/2%“ O
O 0
i7? I78
Intermediate i7? (530 mg, 876 umol, 1.0 eq.), morpholine (80.0 uL, 915 umol, 1.0 eq.) and
N,N-diisopropylethylamine (200 uL, 1.15 mmol, 1.3 eq.) are mixed in itrile (7 mL)
and the resulting mixture is heated at 85 °C overnight. Then, the mixture is allowed to cool
down to room temperature and the solvent is evaporated under d pressure. The
desired product i78 is obtained as a colorless solid (12% yield) after purification by column
chromatography on silica gel (cyclohexane / ethyl acetate 1:0 9 85:15).
1H NMR (400 MHz, CDCI3): 6 7.70 (s, 1 H), 7.59-7.55 (m, 2 H), .31 (m, 6 H), 7.22-
7.16 (m, 2 H), 4.82 (quint, 3JH,H = 6.2 Hz, 1 H), 4.50-4.44 (m, 1 H), 4.09 (dd, 2JHH = 11 Hz,
3.1.”, = 3.1 Hz, 1 H), 3.88 (dd, 2.1.”, = 11 Hz, 3.1.”, = 1.3 Hz, 1 H), 3.69-3.33 (m, 8 H),
1.74 (d, 3JH,H = 6.6 Hz, 3 H), 1.01 (s, 9 H).
Method 32: (E)—4-ethoxy—1,1-difluoro-butenone (i83)
F F F
. /0~ L
ii F 813/081,!» W“ 4:84., Q ,.
” ML,» F 101 F )1” V “‘1
Q O O
To a cooled (-70°C) solution of pyridine (61.5 mL, 760.5 mmol, 1.2 eq) in dichloromethane
(500 mL) is added ethyl vinyl ether (60 mL, 626.5 mmol, 1 eq), followed by a on a
difluoroacetic anhydride (88.5 mL, 760.5 mmol, 1.2 eq) in dichloromethane (75 mL). Then
the mixture is slowly warmed to room temperature overnight. The mixture is transferred
into a separating funnel and the organic layer is washed with water (6x800 mL) until the
pH of the s layer becomes neutral. The organic layer is dried over sodium e
and solvent is removed under reduced pressure to afford the desired product i83 as an
orange oil (76.7 g, 81%). 1H NMR (400 MHz, DMSO-de): 6 7.92 (d, 3JHH = 12.5 Hz, 1H),
6.34 (t, 2.1.,F = 53.6 Hz, 1H), 5.87 (d, 3.1,), = 12.5 Hz, 1H), 4.14 (q, 3.1,), = 7,1 Hz, 2H), 1.28
(t, 3.1,), = 7,1 Hz, 3H); 19F {1 H} NMR (400 MHz, DMSO-de): 6 -127.39 (s, 2F).
Method 33: E difluorometh lethox h drox - entenenitrile i84
is 1:
~ 1 0H
WM 4... 0
“A“ qufflhltbx'“ ‘M [M N‘Mt/k 11/ ”j”
F F "NV
i83 i84
To a cooled (-70°C) solution of n-butyl lithium 2.5M (102.9 mL, 256.7 mmol, 1 eq) in
tetrahydrofuran (435mL) is added acetonitrile (13.4 mL, 256.7 mmol, 1 eq). A white
suspension is formed and is stirred at -70°C for 1h30. A solution of ethoxy-1,1-
difluoro-butenone (i83) (38.5 g, 256.7 mmol, 1 eq) in tetrahydrofuran (65 mL) is
added to the white suspension (mixture beoomes an orange solution). The mixture is
stirred at -70°C for 1h and slowly warmed to room temperature. Water (400 mL) is added.
Then ethyl acetate (600 mL) is added. Layers are separated and aqueous layer is
extracted with ethyl acetate (3X600 mL). Combined c layers are dried over sodium
sulfate and solvent is evaporated under d pressure. Filtration on a short pad of
silica gel, using a mixture of cyclohexane/ethyl acetate (3:1) as eluent, g'ves the desired
product i84 as a dark orange oil (43.4 g, H NMR (400 MHz, DMSO-ds): 6 6.66 (d,
, = 12.8 Hz, 1H), 6.20 (s, 1H), 5.79 (t, 2.1.,F = 55.8 Hz, 1H), 4.75 (d, 3.1.8., = 12.8 Hz,
1H), 3.74 (q, 3.1.8., = 7.0 Hz, 2H), 2.88 (d, 3.1.8., = 16.8 Hz, 1H), 2.81 (d, 3.1.8., = 16.8 Hz,
1H), 1.21 (t, 3.1.8., :70 Hz, 1H); 19F {1H} NMR (400 MHz, DMSO-de): 6 -129.32 (d, ZJF; =
311.2 Hz, 1F), -130.05 (d, 2JP; = 311.2 Hz, 1F).
Method 34: 4-(difluoromethyl)pyridinamine (i65)
R. [F
F 1
M1. eff/Em ”3K /,/ ,, w»
F ‘ r
_... Q 1
3. N NH?
AQ‘N
i84 i65
To a solution of (E)—3-(difluoromethyl)ethoxyhydroxy-pentenenitrile (i84) (8.1 g,
42.4 mmol, 1 eq) in acetic acid (80 mL) is added O-methylhydroxylamine hydrochloride
(Fluorochem, product number 078603) (10.6 g, 127.2 mmol, 3 eq). Mixture is stirred at
50°C for 7h. Then on mixture is cooled down to room ature and hydrobromic
acid in acetic acid (33%) (14.2 mL, 84.8 mmol, 2 eq) is added. Reaction mixture is stirred
at 90°C overnight. Reaction e is degassed and placed under nitrogen. Reaction
mixture is maintained at room temperature with a water bath with ice while zinc powder
(8.12 g, 127.2 mmol, 3 eq) is added portionwise. Reaction mixture is stirred 3 h at room
temperature. Mixture is filtered over a short pad of celite and the cake is washed with ethyl
acetate. Then the major part of the solvent is removed under reduced pressure. 60 mL of
aqueous ammonium hydroxide (28%) is added. s layer is extrated with
dichloromethane (3x150 mL). Combined organic layers are dried over sodium sulfate.
Compound i65 is recrystallized from dichloromethane and heptane as anti-solvent
(solvent switch at the rotavap). Compound i65 is collected, as a light yellow solid, by
filtration (5.12 g, 84%).
Preparation of nds of the Invention
i2 i68 1
According to general procedure 1, compound 1 is obtained from starting materials i2 and
i68 in 73% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.02 (s, 1 H), 7.65 (t,
2JHf = 55 Hz, 1 H), 6.83 (s, 1 H), 4.85 (br s, 2 H), 3.89-3.79 (m, 8 H), 3.77-3.72 (m, 8 H);
19F NMR (376 MHz, : 8 — 115.9 (s, 2 F); MS ): m/z = 393.9 ([M+H]+).
Example 2: 4- difluorometh l 4 6-dimor holino-1 3 5-triazin l rimidinamine 2
o .o.
F ,. 4‘0 .1 F “f LT]
w<\ F /F
Br j :\H< \
,, ,\ é _ B
)1 ‘3“ ——> 0, n ) + ——————————————————————>
. fl .......NW.......LN
N‘ ‘4 N(BOC)2 c)2 l N { .M
j 0 v) 0“" N‘A‘NHz
i71 i2 2
According to general procedure 2, compound 2 is obtained from starting materials i2 and
i71 in 74% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.20 (s, 1 H), 7.62 (t,
ZJHf = 54 Hz, 1 H), 5.97 (br s, 2 H), 3.91-3.68 (m, 16 H); 19F NMR (376 MHz,
CDCI3): 8 — 121.5 (s, 2 F); MS (MALDI): m/z = 395.2 ([M+H]+).
e 3: 5- 4- 3-oxa-8—azabic clo 3.2.1 octan-8— l 3-oxa-8—azabic clo 3.2.1 octan-
8— l-1 3 5-triazin l difluorometh l ridinamine 3
O 0.x
EN j”m" 3L0 _’"”"\
ENE/F [N2]
,3},
N /;<”\O/é ‘/}§:~\\¢ «'11: F‘\ [,F
(,3... A \Na
+ ll ‘1 .
; l;
,. k /l\ j
M.“ x .~
g {/ N N Cl N N: f
f / N N
0.3%) )4
/ o E if,\l
l? ._
v / N NH2
i1 i68 3
According to general procedure 1, compound 3 is obtained from starting materials i1 and
i68 in 75% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.04 (s, 1 H), 7.71 (t,
2JHf = 55 Hz, 1 H), 6.83 (s, 1 H), 4.89 (br s, 2 H), 4.71-4.64 (m, 4 H), 3.79-3.76 (m, 4 H),
3.67-3.62 (m,4 H), .98 (m, 8 H); 19F NMR (376 MHz, CDCI3): 6 — 115.4-(— 117.3)
(m, 2 F); MS ): m/z = 446.3 +).
difluorometh l ridinamine 4
f0xtEEJ”MK l
\ { C)lfl/W,‘
“Kymq FR‘E/ F LINN/V
N/“X‘N O N'MLV‘N E...... F
,1 2i i ..
- y ,1 l
E N N</ “m,C1 "mNV \‘Té {if m If / xN7 j
O V\//) *~. / O / mNC”?
V NHZ
1 0 {El
i 1 2 i68 4
According to general procedure 1, compound 4 is obtained from starting materials i12 and
i68 in 57% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.03 (s, 1 H), 7.68 (m,
1 H), 6.83 (s, 1 H), 4.94 (br s, 2 H), 4.70-4.65 (m, 2 H), 3.93-3.57 (m, 12 H), 2.14-1.92 (m,
4 H); 19F NMR (376 MHz, CDCI3): 8 — 116.0-(— 116.2) (m, 2 F); MS (MALDI): m/z = 420.6
([M+H]+)-
i71 i12 5
According to general procedure 2, compound 5 is obtained from starting als i71 and
i12 in 50% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.23 (s, 1 H), 7.65 (t,
2JH,F= 54 Hz, 1 H), 5.66 (br s, 2 H), 4.68 (m, 2 H), 3.90-3.61 (m, 12 H), 2.13-1.92 (4 H);
19F NMR (376 MHz, CDCI3): 6 — 120.4-(—121.5) (m, 2 F); MS (MALDI): m/z = 420.9
([M+H]+)-
i3 i68 6
According to l procedure 1, compound 6 is obtained from starting materials i3 and
i68 in 79% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 8.87 (s, 1 H), 7.70 (t,
2JHf = 55 Hz, 1 H), 6.86 (s, 1 H), 5.48 (br s, 2 H), 4.73-4.72 (m, 2 H), 4.41-4.38 (m, 2 H),
3.98 (dd, JH,H = 11.6, 3.8 Hz, 2 H), 3.78 (d, JHH = 12 Hz, 2 H), 3.67 (dd, JHH = 12, 3.2 Hz,
2 H), 3.52 (td, JHH = 12, 3.0 Hz, 2 H), 3.27 (td, JHH = 13, 3.8 Hz, 2 H), 1.33 (d,
3JHH = 6.8 Hz, 6 H); 19F NMR (376 MHz, CDCI3): 8 — 115.4-(—116.2) (m, 2 F);
MS (MALDI): m/z = 421.9 ([M+H]+).
Example 7: 5-(4,6-bis((S)—3-methylmorpholino)—1,3,5-triazinyl)
(difluoromethyl)pyrimidinamine_(1)
r-x s: >120 R} g LN)» L/N-u.
Br. ,1 :p\ /L l l L F F
"' O, 1% \{l/ “5:: V? ; + N xN —*
'x, ,4 Q \1
t K {5*\ ; \N/JKCI/,j, A, $93: ,
, /
N N(BOC)2 N 2 f ‘fir { r}: “N l/ \N
J 0 v" 0 v"
N NH?
I71 i3 7
According to general procedure 2, compound 7 is obtained from starting materials W1 and
i3 in 52% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.24 (s, 1 H), 7.66 (t,
2JHf = 54 Hz, 1 H), 5.77 (br s, 2 H), 4.73 (br s, 2 H), 4.45-4.32 (m, 2 H), 3.98 (dd,
JHH = 12, 3.6 Hz, 2 H), 3.78 (d, JHH =12 Hz, 2 H), 3.67 (dd, JHH = 11, 2.8 Hz, 2 H),
3.52 (td, JHH = 12, 2.8 Hz, 2 H), 3.27 (td, JHH =13,3.2 Hz, 2 H), 1.33 (d, 3JH,H = 6.8 Hz,
6 H); 19F NMR (376 MHz, CDCI3): 8 — 120.5-(— 122.7) (m, 2 F); MS ): m/z = 423.3
([M+H]+)-
Example 8: S difluorometh l 4- 3-meth lmor holino mor holino-1 3 5-triazin
yl)pyridinamine (8)
“0., «521‘? {co
._ R» 1 1 1» l l
NNR +
mmmmmmmmmmmmmmmmmmmI»
/‘ 0&3fo $791 x1: F» “F
/.\N}I§,Ni0l \ .MN
N )1
g, ., 11%“?ka
xv,/l "f‘ g [i ll,“ L
V N NH2
i13 i68 8
According to general procedure 1, compound 8 is obtained from starting materials H3 and
i68 in 47% yield as a ess solid. 1H NMR (400 MHz, CDCI3): 8 9.03 (s, 1 H), 7.70 (t,
2JHf = 55 Hz, 1 H), 6.84 (s, 1 H), 4.78 (brs, 2 H), 4.75 (m, 1 H), 4.42-4.38 (m, 1 H), 4.00-
3.96 (m, 1 H), 3.84366 (m, 10 H), 3.55-3.50 (m, 1 H), 3.30-3.25 (m, 1 H), 1.33 (d,
3.1,”, = 6.8 Hz, 3 H); 19F NMR (376 MHz, CDCI3): 5 — 116.1-(-115.9) (m, 2 F);
MS (MALDI): m/z = 408.9 ([M+H]+).
Example 9: S difluorometh l 4- 3-meth lmor holino mor holino-1 3 5-triazin
yl)pyrimidinamine (9)
Ck /O.,
l i
F F \L F F l r l l u
0 <9 i N N
Br\ j 1 «x /8\ / l J. ,L F F
“N . 0 3.14."N l
L‘l + N'QN ——> N"“‘N
,L- l .1! I
1: .2: /, l
N N(Boc)2 N N(Boc)2 \N/ \N \
1 CE 'N“ \N "Cl 'EN
1 O ,1 l A
J ” NV ~\Ni—Iz
I71 H3 9
According to general ure 2, compound 9 is ed from ng materials i71 and
H3 in 60% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.24 (s, 1 H), 7.66 (t,
2JHf = 54 Hz, 1 H), 5.67 (br s, 2 H), 4.74 (m, 1 H), 4.41-4.38 (m, 1 H), 4.00-3.97 (m, 1 H),
3.90-3.72 (m, 9 H), 3.68-3.36 (m, 1 H), 3.56-3.49 (m, 1 H), 3.32-3.25 (m, 1 H), 1.33 (d,
3JH,H = 6.9 Hz, 3 H); 19F NMR (376 MHz, CDCI3): 8 — 121.3-(— 121.6) (m, 2 F);
MS (MALDI): m/z = 409.4 ([M+H]+).
Example 10: 5- 4- 3-oxaazabic clo 3.2.1 octan l S meth lmor holino -1 3 5-
n l difluorometh l ridinamine 10
(ckl o]l
W“: 394%? Ri F
B If
O l: / N F F
‘3’: L” + Ll »
: ‘l ’E‘ 1
:3 a N: 3:3 N: :1
o \ ‘7“ 03...: MN» NHE
i18 i68 10
According to general procedure 1, compound 10 is ed from starting materials H8
and i68 in 42% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.04 (s, 1 H),
7.69 (t, 2JH,F = 55 Hz, 1 H), 6.84 (s, 1 H), 4.85 (br s, 2 H), 4.71-4.65 (m, 3 H), 4.42-4.39 (m,
1 H), 3.98-3.95 (m, 1 H), 3.79-3.76 (m, 3 H), 3.70-3.65 (m, 3 H), 3.56-3.53 (m, 1 H), 3.30-
3.27 (m, 1 H), 2.10-1.99 (m, 4 H), 1.33 (m, 3 H); 19F NMR (376 MHz, CDCI3): 6 —115.9—
(—116.2) (m, 2 F); MS (MALDI): m/z = 434.2 ([M+H]+).
Example 11: 5- 4- 3-oxa-8—azabic clo 3.2.1 8- l S meth lmor holino -1 3 5-
triazin l difluorometh l rimidinamine 11
According to general procedure 2, compound 11 is obtained from ng materials i71
and H8 in 46% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.25 (s, 1 H),
7.68 (t, 2JHf = 55 Hz, 1 H), 5.81 (br s, 2 H), 4.71-4.65 (m, 3 H), 4.42-4.38 (m, 1 H), 4.00-
3.96 (m, 1 H), .60 (m, 6 H), 3.55-3.50 (m, 1 H), 3.31-3.24 (m, 1 H), 2.11-2.00 (m,
4 H), 1.37-1.28 (m, 3 H); 19F NMR (376 MHz, CDCI3): 8 — 121.5-(— 121.7) (m, 2 F);
MS ): m/z = 434.6 ([M+H]+).
Example 12: 4- difluorometh l 4-mor holino i erazin l -1 3 5-triazin
yl)pyridinamine (12)
2015/076192
(.13.; o
l I
JO F F
l l
,,,,,
N N
;><\O"é‘“ l NAN N/igr F3 /F
1% L it (i. —*
A; 1: FL L
r) N N '1 1’ l “1
\\ OWWVNX ”NM-r"""
F? N NH2
H4 i68 12
ing to general procedure 1, compound 12 is obtained from starting materials i68
and H4 in 86% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.85 (s, 1 H),
7.74 (t, 2JHF = 55 Hz, 1 H), 6.84 (s, 2 H), 6.75 (s, 1 H), 3.82-3.70 (m, 8 H), 3.69-3.60 (m,
4 H), 2.88-2.80 (m, 4 H); 19F NMR (376 MHz, (CD3)ZSO): 8 — 115.4 (s, 2 F); MS (MALDI):
m/z = 393.8 ([M+H]+).
Example 13: 4- difluorometh l 4-mor holino i l -1 3 5-triazin
yl)pyrimidinamine (13)
F} F \:;;.\0 FT F % LY] [Vi
BR i F F
N D /\O/B N E + Nf‘N w’ NAN
t J , l 5 1 Fl ,1; ,1 l;
N N(Boc)2 l N" Nags»; 3 r}: N or i bl} N T
i J} .OWWNK HNV U
N FNHZ
i71 H4 13
According to general procedure 2, compound 13 is obtained from starting materials i71
and H4 in 55% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.23 (s, 1 H),
7.64 (t, 2JHF = 55 Hz, 1 H), 5.60 (br s, 2 H), 3.83-3.75 (m, 12 H), 2.94-2.88 (m, 4 H);
19F NMR (376 MHz, CDCI3): 8 — 111.4 (s, 2 F); MS (MALDI): m/z = 395.1 ([M+H]+).
Example 14: S difluorometh l 4- 3-meth lmor holino i erazin l -1 3 5-
triazin l ridinamine 14
to l ‘
l/ «>ch FF,
1‘:,.
/ N,
“0’8” F
”55‘? g; NM“ F\
+ l —>
n is ,. ll ,1 l
[// 3’.» ‘x.Cl N/ Nb“! ”\xww \N’/W\Vl 1
+0 TE/N.V “I‘lj/ HNx/
N \NH2
i21 i68 14
According to general procedure 1, compound 14 is obtained from starting materials i21
and i68 in 47% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.02 (s, 1 H),
7.67 (t, 2JH,F = 56 Hz, 1 H), 6.84 (s, 1 H), 4.90 (br s, 2 H), 4.74 (s, 1 H), 4.40 (d, JH,H =
16 Hz, 1 H), 3.98 (dd, JH,H= 4.0 Hz, 12 Hz, 1 H), 3.91 (m, 4 H), 3.78 (d, JH,H = 12 Hz, 1 H),
3.68 (dd, JHFH = 4.0, 12 Hz, 1 H), 3.56 (t, JH,H = 4.0 Hz, 1 H), 3.26 (dt, JH,H = 4.0, 12 Hz,
1 H), 2.99 (t, JH,H = 4.0 Hz, 4 H), 1.32 (d, JH,H = 8.0 Hz, 3 H);19F NMR (376 MHz,
CDCI3): 8 — 115.9 (s, 2 F); MS ): m/z = 407.2 ([M+H]+).
Example 15: S difluorometh l 4- 3-meth lmor holino
triazin l rimidinamine 15
_ o.
F F \I l t, J L
_/, f' O F K, F
\ N
Br\ >8 F /L~, F\
SN ' é JR
' o N N
l w, \‘N N ‘N
+ m
A. J;F' A: J A
A ,l' A L
N/\N(Boc);; ‘N/“Meocb ( "f N Cl f N N' “‘1' ‘N
0\ ,N\ /} HN J L
\ ,fi\
\N‘ ‘“
W. [f NH2
i71 i21 15
According to general procedure 2, compound 15 is ed from starting materials i71
and i21 in 30% yield as a colorless solid. 1H NMR (400 MHz, : 8 9.24 (s, 1 H),
7.66 (t, 2JH,F = 56 Hz, 1 H), 5.69 (br s, 2 H), 4.74 (s, 1 H), 4.40 (d, JH,H = 16 Hz, 1 H), 4.38
(dd, JH,H = 4.0, 12 Hz, 1 H), 3.83 (m, 4 H), 3.78 (d, JH,H =12 Hz, 1 H), 3.68 (dd, JH,H = 4.0,
12 Hz, 1 H), 3.54 (dt, JH,H = 4.0, 12 Hz, 1 H), 3.28 (dt, JH,H = 4.0, 12 Hz, 1 H), 2.92 (t,
JH,H = 8.0 Hz, 4 H), 1.33 (t, JH,H = 8.0 Hz, 3 H); 19F NMR (376 MHz, CDCI3): 8 — 121.4 (s,
2 F); MS (MALDI): m/z = 408.7 ([M+H]+).
Example 16: 4- difluorometh l 2 6-dimor holino rimidin l 2-amine 16
FFFFF
{\TA f [.ani
“mg”? 13le\. T}
/ \‘A B F
N O """"" NF?
N ":15? F”\, ,x
J J J. A W J: ,3 J.
N ”N/“c: “N’ ‘N f “N N ”‘W‘
o J K Q J J? J
/ I? ’
“8 “N’ “MHZ
i22 i68 16
According to general procedure 1, compound 16 is obtained from starting materials i22
and i68 in 73% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 8.31 (s, 1 H),
7.30 (t, 2JH,F = 55 Hz, 1 H), 6.85 (s, 1 H), 6.04 (s, 1 H), 4.73 (br s, 2 H), 3.81-3.72 (m,
2015/076192
12 H), 3.65-3.59 (m, 4 H); 19F NMR (376 MHz, CDCI3): 5 — 115.1 (s, 2 F); MS (MALDI):
m/z = 394.3 ([M+H]+).
/O\,
F F J.. F /F LN J LNJ
i “V,” 9 l l l
Br '/\Q”B\/ N/ N/‘fil‘ F l:
/ \N V
l ' + '
J l ,,,1 J
f A ”N Q /J\ x
N )2 N 2 N N Cl r N N )1 N
o o. ,l I K
N NH2
I71 i22 17
According to general procedure 2, compound 17 is ed from starting materials i71
and i22 in 7% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 8.60 (s, 1 H),
7.11 (t, 2JHf = 55 Hz, 1 H), 6.02 (s, 1 H), 5.46 (br s, 2 H), 3.80-3.74 (m, 12 H), 3.64-
3.60 (m, 4 H); 19F NMR (376 MHz, CDCI3): 5 — 119.5 (s, 2 F); MS (MALDI): m/z = 394.3
([M+H]+)-
i23 i68 18
According to general procedure 1, compound 18 is obtained from starting materials i23
and i68 in 89% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 8.94 (s, 1 H),
7.61 (t, 2JHf = 55 Hz, 1 H), 6.83 (s, 1 H), 5.50 (s, 1 H), 4.74 (br s, 2 H), 3.82-3.78 (m, 8 H),
3.61-3.57 (m, 8 H);19F NMR (376 MHz, CDCI3): 8 — 115.4 (s, 2 F); MS (MALDI):
m/z = 393.3 ([M+H]+).
Example 19: 4'- difluorometh l -4 6-dimor holino— 2 5'-bi rimidin -2'-amine 19
WO 75130
[OR] o
F‘TF ,3L0 FTP l l
"N/ \N
B Amos
l N AN A A F
l *
A A it A ll A L
N ‘N(Boc)2 “N \N(Boc)2 N N c: l/ N N 7' \N
l O /I O\ /J “?L\
J N NH;
i71 i23 19
According to general procedure 2, compound 19 is obtained from starting materials i71
and i23 in 7% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.16 (s, 1 H),
7.58 (t, 2JHf = 55 Hz, 1 H), 5.75 (br s, 2 H), 5.50 (s, 1 H), 3.82-3.79 (m, 8 H), 3.61-3.58 (m,
8 H); 19F NMR (376 MHz, CDCI3): 8 — 121.1 (s, 2 F); MS ): m/z = 395.3 ([M+H]+).
Example 20: 4- difluorometh l 4-mor holino—6-thiomor holino—1 3 zin l -
pyridinamine (20)
[MON] o
A ,F l l
N - A0 w
i "B I i F F
N““‘~“‘N 0‘ K “*1 WAN x.»
l E} _—.,..
m a“: J\ A A; , in ”L
r N N‘ “\Cl N NLi {K i? N/ ll 1
V, 531/ 3m///// "Ni; NHZ
“5 i68 20
According to general procedure 1, compound 20 is obtained from starting materials H5
and i68 in 77% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.02 (s, 1 H), 7.65
(t, J = 55 Hz, 1 H), 6.84 (s, 1 H), 4.83 (br s, 2 H), 4.23-4.07 (m, 4 H), 3.90-3.79 (m, 4 H),
3.79-3.71 (m, 4 H), 2.71-2.62 (m, 4 H); 19F NMR (376 MHz, CDCI3): 8 — 116.0 (s, 2 F);
MS (MALDI): m/z = 410.3 ([M+H]+).
Example 21: 4- rometh l 4-mor holino—6-thiomor holino—1 3 5-triazin l -
pyrimidinamine (21)
l O\ /,.O
l l
FTP N RN”
/\ J
Bu '1’
\ F F
T: 3" AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA> + l?) ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, N N
i ,A-‘\ A75
6. x ,/‘\, ’J/LN
N N(Boc)2 [ I? N Ci (/
{ N N ll N
V s\ ,
\,/ N
_ NH2
According to general procedure 2, compound 21 is obtained from starting materials i71
and HS in 70% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.21 (s, 1 H),
7.60 (t, 2Jim: 54 Hz, 1 H), 5.90 (br s, 2 H), 4.22-4.06 (m, 4 H), 3.91-3.78 (m, 4 H), 3.78-
3.71 (m, 4 H), 2.71-2.62 (m, 4 H); 19F NMR (376 MHz, : 6 — 120.5-(— 121.5) (m,
2 F); MS (MALDI): m/z = 411.2 ([M+H]+).
azabic clo 3.2.1 8- l rimidin l difluorometh l ridinamine 22
i24 i68 22
According to general procedure 1, compound 22 is obtained from starting materials i24
and i68 in 61% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.34 (s, 1 H),
7.55 (t, 2JHf = 55 Hz, 1 H), 6.76 (s, 1 H), 6.60 (br s, 2 H), 6.36 (s, 1 H), 4.64-4.47 (m, 4 H),
3.67-3.49 (m, 4 H), 3.56-3.49 (m, 4 H), 1.98-1.79 (m, 8 H); 19F NMR (376 MHz,
(CD3)ZSO): 8 — 114.9-(— 115.2) (m, 2 F); MS (MALDI): m/z = 445.3 ([M+H]+).
oromethyl)pyridinamine (23)
I(«OW F {WOW}
\TJ \yPL‘ C? F
.....f
/W ,BW «:15 ),.
ll 1 O 22,; WW FW [F
+ i » ‘l
4% ,w x. :7 x“b
'«W x 41m /r» 2x l
/ g W
WW;’2' N N c; N N N N w
1; (5». l
O».\ 04% [l L
/ ‘w /' x 4'
V W, N, NH?
r?
i29 i68 23
According to general procedure 1, compound 23 is obtained from starting als i29
and i68 in 54% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 8.30 (s, 1 H), 7.30
(t, 2JHf = 55 Hz, 1 H), 6.84 (s, 1 H), 6.04 (s, 1 H), 4.85 (br s, 2 H), 4.62 (br s, 2 H), 3.82-
3.74 (m, 6 H), 3.65-3.56 (m, 6 H), 2.09-2.00 (m, 2 H), .91 (m, 2 H);
19F NMR (376 MHz, CDCI3): 8 — 115.2-(—116.2) (m, 2 F); MS (MALDI): m/z = 419.0
([M+H]+)-
i71 i29 24
According to l procedure 2, compound 24 is obtained from starting materials i29
and i71 in 72% yield as a ess solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.71 (s, 1 H),
7.35 (s, 2 H), 7.32 (t, 2JHf = 54 Hz, 1 H), 6.45 (s, 1 H), 4.54 (br s, 2 H), 3.71-3.50 (m,
12 H), .78 (m, 4 H); 19F NMR (376 MHz, (CD3)ZSO): 8 — 119.2 (s, 2 F); MS (MALDI):
m/z = 420.6 ([M+H]+).
Example 25: 5- 2 6-bis S meth lmor holino rimidin l difluorometh l ridin-
2-amine (25)
[flow ,0
N) k1 l
\XM’C? F {F
Ax ,..B\ \> LT F\ A”:
:1 fl O ,/
r ”l J * Ti 1
[ x? Nr/ x0; N {>12 (/ KN , \N
o o t \U, .39
{1’ N “m2
i25 i68 25
According to general procedure 1, compound 25 is obtained from starting materials i25
and i68 in 57% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.31 (s, 1 H),
7.52 (t, 2JHf = 55 Hz, 1 H), 6.76 (s, 1 H), 6.59 (br s, 2 H), 6.30 (s, 1 H), 4.60-4.50 (m, 1 H),
4.44-4.33 (m, 1 H), 4.24-4.15 (m, 1 H), 4.12-4.04 (m, 1 H), 3.94-3.83 (m, 2 H), 3.74-3.64
(m, 2 H), 3.59-3.51 (m, 2 H), 3.45-3.35 (m, 2 H), 3.14-3.02 (m, 2 H), 1.18 (t, 3JH,H = 7.2 Hz,
6 H); 19F NMR (376 MHz, (CD3)ZSO): 8 — 113.7-(— 115.9) (m, 2 F); MS (MALDI):
m/z = 421.1 +).
Example 26: 4'- difluorometh l -2 6-bis S meth lmor holino - 4 5'-bi rimidin -2’-
amine (26)
2015/076192
o. 0
§ f/ ..' x
F\) F \v/LQ F 1 l 1
F\? g x‘N/r \N/ ”"7
Br‘\,/-/2 //\\' F
0”EN/2‘}
1 ,z/llmh x/ilx F\«\
11‘? —* ill? H ”1“) M E‘Tjfll[
\N ‘N(Boc)2 N/ ‘N(Boc)2 i [ N C! [/1 ‘51” ”N/ “a
i O r]: O “““““J K I}:
N NH?
.0, ml
i71 i25 26
ing to general procedure 2, compound 26 is obtained from starting materials i25
and i71 in 56% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 8.60 (s, 1 H), 7.14
(t, 2JH,F = 54 Hz, 1 H), 5.98 (s, 1 H), 5.48 (br s, 2 H), 4.71-4.62 (m, 1 H), .23 (m,
2 H), 4.08-3.92 (m, 3 H), 3.83-3.65 (m, 4 H), 3.61-3.49 (m, 2 H), 3.25 (dt, 2JH,H =13 Hz,
3.1,”, = 3.6 Hz, 2 H), .27 (m, 6 H); 19F NMR (376 MHz, 00013): 8 — 119.5 (s, 1 F),
119.7 (m, 1 F); MS (MALDI): m/z = 423.0 ([M+H]+).
Example 27: S difluorometh l 6- 3-meth lmor holino mor holino rimidin
yl)pyridinamine (27)
[AEJ F \ IEKJ
\ )1“? Fa?8
,,,,,,, 1,0 ,3 4 r/,,»g:%
:EJL”a“515 1 jfix \
Fx/F
A {1% ,f"\ /1\«‘ “La
E lTl N Cl N if? I? 1 N
CK / j;
Mw/ CLV, \ Ne”?
i30 i68 27
According to general procedure 1, compound 27 is obtained from starting materials i30
and i68 in 74% yield as a ess solid. 1H NMR (400 MHz, CDCI3): 8 8.31 (s, 1 H), 7.30
(t, 2.0,; = 55 Hz, 1 H), 6.85 (s,1 H), 6.02 (s, 1 H), 4.75 (brs, 2 H), 4.35-4.25 (m, 1 H),
4.06-3.96 (m, 2 H), 3.83-3.69 (m, 10 H), 3.58 (dt, 2.1,”, = 12 Hz, 3.1,”, = 3.2 Hz, 1 H), 3.25
(dt, 2.0,), = 13 Hz, 3.1,”, = 3.8 Hz, 1 H), 1.31 (d, 3.1,”, = 6.8 Hz, 3 H); 19F NMR (376 MHz,
CDCI3): 8 — 114.9-(— 115.0) (m, 2 F); MS (MALDI): m/z = 407.1 ([M+H]+).
Example 28: S -4'- difluorometh l 3-meth lmor holino mor holino— 4 5'-
bi rimidin -2’-amine 28
x’O\-.,_ O
VJ .9
F L l F F \ F\
BM 1 V" J3». f t 23
,/ O ,/ (1.. ,,.g F F
{g N N
—» )1 + mmmmmmmmmmmmm+
4m '
x a. 1))
,- 1.. l} “
f k, 1
N N(Boc)z N N<Boc)2 {
N/ Cl E' N
0 If OL
t? 1Ei {El
, \N, «g
1 N NHg
i71 i30 28
ing to general procedure 2, compound 28 is obtained from starting materials i30
and i71 in 53% yield as a ess solid. 1H NMR (400 MHz, CDCI3): 8 8.60 (s, 1 H), 7.13
(t, 2./H,F= 54 Hz, 1 H), 6.01 (s,1 H), 5.47 (brs, 2 H), 4.71-4.63 (m,1 H), 4.31 (dd,
2.1,”, = 14 Hz, 3.1,”, = 2.4 Hz, 1 H), 3.97 (dd, 2.1,”, = 11 Hz, 3.1,”, = 3.4 Hz, 1 H), 3.79 (t,
3.1,”, = 4.6 Hz, 4 H), 3.72-3.66 (m, 2 H), 3.65-3.58 (m, 3 H), 3.58-3.50 (m, 2 H), 3.30-3.21
(m, 1 H), 1.30 (d, 3.1,”, = 6.8 Hz, 3 H); 19F NMR (376 MHz, 00013): 6 — 119.7 (brs, 2 F);
MS (MALDI): m/z = 408.9 ([M+H]+).
Example 29: 5-(4-(8-Oxaazabicyclo[3.2.1]octanyl)(8-oxa
azabicyclo[3.2.1]octanyl)-1,3,5-triazinyl)(difluoromethyl)pyridinamine 29
l Ejo.
x/‘imO“N F\”‘ “F 2.x“
jg 5 E i. F F
Odddddd 1’ ~43: N \‘N \ /"
+ F l —> :1 9:, L
.1 N N1 1 N N“ 1
16,, J 1,1 1
,, \O N 4,1
19,911 321 xvi? N’ NHZ
i81 i68 29
According to general ure 1, compound 29 is obtained from starting materials i68
and i81 in 89% yield as a colorless solid. 1H NMR (400 MHz, : 89.03 (s, 1 H),
7.69 (t, 2JH,F = 55 Hz, 1 H), 6.83 (s, 1 H), 4.85 (br s, 2 H), 4.50-4.24 (m, 8 H), 3.28-3.12 (m,
4 H), 1.94 (br s, 4 H), 1.86-1.71 (m,4 H); 19F NMR (376 MHz, CDCI3): 8 — 115.1-(—117.2)
(m, 2 F); MS (MALDI): m/z = 446.3 ([M+H]+).
Example 30: 5-[4,6-bis(2,2-dimethylmorpholinyl)-1,3,5-triazinyl]—4-
(difluoromethyl)pyridinamine 30
1 63
/»O.\}// O \lx/
[ F F I
./ Nix/7‘0 j
31 xx -é. L
0 / x T
/' £3» \ Fxx / F
*1 ”'3‘ + l W
N N l
/ \ch \C! t
+ \N am?“ / Nam \R
1 U» i ll .l
0V" I? 0‘» f N” ‘NHZ
i80 i68 30
According to general procedure 1, compound 30 is obtained from ng materials i68
and i80 in 63% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.86 (s, 1 H),
7.71 (t, 2JHf = 55 Hz, 1 H), 6.84 (brs, 2 H), 6.76 (s, 1 H), 3.81-3.56 (m, 12 H), 1.14 (s,
12 H); MS ): m/z = 451.2 ([M+H]+).
Example 31: S difluorometh l 2- 3-meth lmor holino mor holino rimidin
yl)pyridinamine (31)
0. ,ox
{ /] 3'3“ F { }
N xii:0 / RN
1 >4 g; I l
'\ x/"im? .x xx. Fx, F
N a ’0 N :
“ ll l
,. A L l
/ ,,,,,,,, ; “ / ” .
i N Cl N l: f N N i/ x
O .V/j / Q w/l \L
N N NH2
1 0 l
i28 i68 31
According to l procedure 1, compound 31 is obtained from ng materials i28
and i68 in 58% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.31 (s, 1 H),
7.52 (t, 2JHf = 55 Hz, 1 H), 6.74 (s, 1 H), 6.59 (br s, 2 H), 6.35 (s, 1 H), 4.59-4.51 (m, 1 H),
4.22-4.14 (m, 1 H), 3.91-3.84 (m, 1 H), 3.72-3.50 (m, 10 H), 3.44-3.35 (m, 1 H), 3.14-3.03
(m, 1 H), 1.16 (d, 3.1,”, = 6.7 Hz, 3 H); 19F NMR (376 MHz, (003)280): 5 — 113.7-(—115.3)
(m, 2 F); MS (MALDI): m/z = 407.1 ([M+H]+).
Example 32: S -4’- difluorometh l 3-meth lmor holino mor holino— 4 5’-
bi rimidin -2’-amine 32
l/o.\ (,0
F F L I 1
r 410 ka/F ix
B i B J
“xx / ~ /”¢ E '3’
\ ”:2 /. ,_ . ,
1 i O
—> ‘2’ + l1 ~~~~~~~~~~., 1 if
.x x ///\ ,1, j. j:k
‘N’ N(BoC)2 N Mama); 1“" N” “N“ Cl 7’ N N ii N
0.. J ox J
V V N NHZ
According to general procedure 2, compound 32 is obtained from starting materials i28
and i71 in 63% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 8.60 (s, 1 H), 7.13
(t, 2.13,; = 54 Hz, 1 H), 5.99 (s, 1 H), 5.46 (br s, 2 H), 4.34-4.25 (m, 1 H), 4.06-3.97 (m,
2 H), .68 (m, 10 H), 3.58 (dt, 2.13”, = 12 Hz, 3.133, = 3.2 Hz, 1 H), 3.26 (dt, 2.13”, =
13 Hz, 3.133, = 3.7 Hz, 1 H), 1.31 (d, 3.133, = 6.8 Hz, 3 H); 19F NMR (376 MHz, (CD3)280):
8 — 119.5 (s, 2 F); MS (MALDI): m/z = 408.7 ([M+H]+).
Example 33: 4-(difluoromethyl)—5-[4-[(2S,6R)—2,6-dimethylmorpholinyl]—6-[(3R)—3-
morpholinyl]-1,3,5-triazinyl]pyridinamine 33
,0... o
3 f
k \L F. ,1: 3
3 .3, 3
O “3k
33 + ‘l; —> 33 F
\XAWN “N": “C: N 31 \/MN “31"“U/ <31
0 (3 N (5- /3 L 3"
N NH;
31/ ”I”
i82 i68 33
ing to general procedure 1, compound 33 is obtained from starting materials i68
and i82 in 71% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.74 (t, 2J3); = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.71-4.62 (m, 1 H), 4.45-4.34 (m,
2 H), 4.31-4.09 (m, 1 H), 3.90 (m, 1 H), 3.71 (m, 1 H), 3.55 (m, 3 H), 3.38 (m, 1 H),
3.13 (m, 1 H), 2.55 (m, 2 H), 1.20 (d, 3JH,H = 6.9 Hz, 3 H), 1.19 (d, 3JH,H = 6.9 Hz, 6 H); MS
(MALDI): m/z = 436.1 ([M+H]+).
Example 34: 5-[4,6-bis[(2R,6S)—2,6-dimethylmorpholinyl]-1,3,5-triazinyl]
(difluoromethyl)pyridinamine 34
Toff v.03 3 303/
‘3 :31. 3 3. '1‘
$3,233?“ 0
+ NE “3] N/QXN Fix/3F
\5/ N 3N \[3 3 33 3 N” N” Cl l3 N N
O 3/3 \N/ Ox. .3”; U”
<. 23L.
1 3 I N NH2
i79 i68 34
ing to general procedure 1, nd 34 is obtained from starting materials i68
and i79 in 75% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.86 (s, 1 H),
7.71 (t, 2JHf = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.64-4.46 (m, 4 H), 3.60-3.48 (m,
4 H), 2.63 (m, 4H), 1.14 (m, 12 H); MS (MALDI): m/z = 450.0 ([M+H]+).
Example 35: 4- 4- 6-amino difluorometh | rid | mor holino—1 3 5-triazin
Imor holinone 35
{N1 . (N1
N/RN gig. 0’B \ NANF F
(\N [NACI 1N/ N (\N IN%
ovko KYl 0&0 l
N/ NH2
i31 i68 35
According to l procedure 1, compound 35 is obtained from starting materials i31
and i68 in 10% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.08 (s, 1 H), 7.96
(t, 2JHf = 56 Hz, 1 H), 6.86 (s, 1 H), 4.98 (br s, 2 H), 4.35 (s, 2 H), 4.07-4.00 (m, 4 H), 3.95
(br s, 2 H), 3.90 (br s, 2 H), 3.78 (br s, 4 H);19F NMR (376 MHz, CDCI3): 8 — 117.4 (s, 2 F).
Example 36: 4- 4- 2-amino rometh | rimidin | mor holino—1 3 zin
yllmorpholin-B-one (36)
o o
F F
QL F F U [1
\ C? 1
hi F
—* “‘
N NEsoc2 0311 / 111%/ /
N NBOC2 fN N CI N N i\N
0&0 0A0 NANHZ
i71 i31 36
ing to general procedure 2, compound 36 is obtained from starting materials i31
and i71 in 6% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 9.22 (s, 1 H),
8.10 (t, 2JHf = 56 Hz, 1 H), 7.97 (br s, 2 H), 4.28 (s, 2 H), 3.98 (s, 4 H), 3.90 (br s, 2 H),
3.81 (br s, 2 H), 3.70 (br s, 4 H); 19F NMR (376 MHz, (CD3)280): 8 — 121.1 (s, 2 F); MS
(MALDI): m/z = 408.7 ([M+H]+).
Example 37: 5- 4 6-bis 3 7-dioxaazabic c|o 3.3.1 nonan | -1 3 5-triazin |
(difluoromethyl)pyridinamine (37)
R ,0 R R
J t X “j
x, x
\4’ , a
. ’ ! \1” }‘
Ext/y /}\Q Fx F iv,
,é T: j
,i, O‘ R; m , R a F
N ‘~ N + ,g 1 ___________________,, §
,ii ,/Jx KM NI} \‘N x” \ N14 “N ,»/Z?::,..
-__,,,.N/ "N” “c: gg FT“ B l
0/ TY
‘ E j N NH2
0/1,... 0’
i7 i68 37
According to general procedure 1, compound 37 is obtained from starting materials i7 and
i68 in 39% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.85 (s, 1 H), 7.68
(t, 3JH,F = 55 Hz, 1 H), 6.87 (br s, 2 H), 6.74 (s, 1 H), 4.51 (br s, 2 H), 4.45 (br s, 2 H), 4.07-
3.93 (m, 8 H), 3.79-3.67 (m, 8 H); 19F NMR (376 MHz, (CD3)280): 8 — 115.8 (s, 2 F); MS
(MALDI): m/z = 478.1 ([M+H]+).
i35 i68 38
According to general procedure 1, compound 38 is obtained from starting materials i35
and i68 in 67% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.73 (t, 3JH,F = 55 Hz, 1 H), 6.87 (br s, 2 H), 6.75 (s, 1 H), 4.70-4.54 (m, 2 H), .43 (m,
2 H), 4.05-3.97 (m, 4 H), .67 (m, 4 H), 3.63-3.55 (m, 4 H) 2.00-1.83 (m, 4 H);
19F NMR (376 MHz, (CD3)280): 8 — 115.8 (s, 1 F), — 115.9 (s, 1 F); MS (MALDI):
m/z = 462.1 +).
Example 39: 5- 4 6-bis 3 3-dimeth lmor holin l -1 3 5-triazin l
(difluoromethyl)pyridinamine (39)
vvvvv 0‘21
[MN 1
NFL”Q FTP Law/K
1 ,1 L 1: 1:
’ “‘1“ 0 1 N”““~“N /
:2! {TL j: + 1 7t 1;,
flflflflflflflflflflflflflflflflflflflflflflflflflflflflflflfl, [\ 3% /i\ 1
1" N 01 N { N
O»’’’’’’’I?
1:1! 511 1 *1
[13/ O\“’/ “ N” ““NHg
i4 i68 39
According to general procedure 1, compound 39 is obtained from starting materials i4 and
i68 in 28% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.78 (s, 1 H), 7.70
(t, 2JHf = 55 Hz, 1 H), 6.82 (br s, 2 H), 6.77 (s, 1 H), 3.87-3.75 (m, 8 H), 3.45 (br s, 4 H),
1.49 (s, 12 H); 19F NMR (376 MHz, (CD3)ZSO): 6 — (— 115.1) (m, 2 F); MS (MALDI):
m/z = 450.1 ([M+H]+).
e 40: 5- 4 6-bis 3R 5S -3 5-dimeth lmor holin l -1 3 5-triazin l
(difluoromethyl)pyridinamine (40)
1 1
1:1. 2 N O 1111:/ \11
1 11 +
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
1 ’ ’ x
g N N Ci N {113 r/ N N
O L». l
,x’ O“xx/K b
,,,,,,,J\ x
I? N NH2
i6 i68 40
According to general procedure 1, compound 40 is obtained from ng materials i6 and
i68 in 42% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.90 (s, 1 H), 7.82
(t, 2JHf = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.77 (s, 1 H), 4.59-4.43 (m, 4 H), 3.82-3.73 (m,
4 H), 3.60-3.51 (m, 4 H), 1.29 (d, 2J1”, = 6.9 Hz, 12 H); 19F NMR (376 MHz, (003)280):
8 — 114.9—(— 115.0) (m, 2 F); MS (MALDI): m/z = 450.2 +).
Example 41: 5- 4 6-bis 3R meth lmor holin l-1 3 5-triazin l
(difluoromethyl)pyridinamine (41)
infik ,J‘o {-1 F
, {NR
J\ ,1/11{1.\ é ) J F F
1 ii “l y
R / “m J1 )i ,4 i1.
r I?! N/ Ci N A; [1” [TI N/
A NE,
ON T 02‘ "/ L
N “NI-12
i5 i68 41
According to general procedure 1, compound 41 is obtained from starting materials i5 and
i68 in 98% yield as a colorless solid. 1H NMR (400 MHz, CDCI3): 8 9.04 (s, 1 H), 7.70 (t,
2.0,; = 52.0 Hz, 1 H), 6.84 (s, 1 H), 4.88 (br s, 2 H), 4.77-4.72 (m, 2 H), 4.41 (d, 2.0,), =
12.0 Hz, 2 H), 3.98 (dd, 2.0,), = 12.0 Hz, 3.0,), = 4.0 Hz, 2 H), 3.78 (d, 2.0,), = 12.0 Hz, 2 H),
3.68 (dd, 2JH,H= 12.0 Hz, 3.0,), = 4.0 Hz, 2 H), 3.53 (dt, 2.1,”, = 12.0 Hz, 3.1,”, = 4.0 Hz, 2 H),
3.28 (dt, 2.0,), = 12.0 Hz, 3.0,), = 4.0 Hz, 2 H), 1.33 (d, 2.0,), = 8.0 Hz, 6 H); 19F NMR
(376 MHz, 00013): 8 — 115.9 (s, 1 F), — 116.0 (s, 1 F); MS (MALDI): m/z = 421.7 ([M+H]+).
e 42: 4- difluorometh l 4- 3 3-dimeth lmor holin l mor holino—1 3 5-
triazinl 2-amine 42
N l 9 6.3,):
((((( \ \T/
/' "' B “ / 25.x /
'1“) 3‘ O
+ t 1 )1
A 3‘“ ii
F. 321/ x, N 8» N?
Cl I} §'/A\[]§ \
N I; \\.1
O‘Nx ”‘1 O
I? \/‘ \ N11? \
i16 i68 42
According to general procedure 1, compound 42 is obtained from starting materials i16
and i68 in 35% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.83 (s, 1 H),
7.73 (t, 2JHf = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 3.85-3.76 (m, 4 H), 3.76-3.63 (m,
8 H), 3.45 (br s, 2 H), 1.49 (s, 6 H); 19F NMR (376 MHz, (CD3)280): 8 — 115.0 / — 116.3 (s,
2 F); MS ): m/z = 423.2 ([M+H]+).
i33 i68 43
According to l procedure 1, compound 43 is obtained from starting materials i33
and i68 in 43% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 9.01 (s, 2 H),
7.81 (t, 2JHf = 55 Hz, 2 H), 7.00 (br s, 4 H), 6.82 (s, 2 H), 4.78-4.66 (m, 1 H), .35 (m,
1 H), 4.01-3.91 (m, 1 H), 3.81-3.72 (m, 1 H), 3.65-3.58 (m, 1 H), 3.52-3.42 (m, 1 H), 3.38-
3.23 (m, 1 H) 1.30 (d, 3.1),), = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)280): 6 — 114.3-
(— 117.2) (m, 4 F); MS (MALDI): m/z = 465.1 ([M+H]+).
i37 i68 44
According to general procedure 1, compound 44 is obtained from starting materials i3?
and i68 in 75% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.89 (s, 1 H),
7.79 (t, 2JHf = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.65 (brs, 1 H), 4.50 (br s, 2 H),
4.37-4.25 (m, 1 H), 3.93 (dd, 3JH,H = 11 Hz, 3JH,H = 3.2 Hz, 1 H), 3.79-3.67 (m, 3 H), 3.59-
3.51 (m, 3 H), 3.45-3.36 (m, 1 H), 3.22-3.11 (m, 1 H), 1.30 (d, 3JH,H = 6.7 Hz, 6 H), 1.24 (d,
3.1),), = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)280): 6 — 115.0 (br s, 2 F); MS (MALDI):
m/z = 436.1 ([M+H]+).
o\ ,,o
{”ml/k LN \3 Q;~~~~o 1:ng
i. K is i L
\ O / 1:, F
\ N \\N x /
I//Nr§N/SJ t, + M N/J ”D
C! \N ’16:)!“ng \, /L
J 1L CE, 1 l: ,L
1? v N ‘NHZ
i38 i68 45
According to general procedure 1, compound 45 is obtained from starting materials i38
and i68 in 71% yield as a ess solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.84 (s, 1 H),
7.74 (t, 2.1),,F = 55 Hz, 1 H), 6.63 (br s, 2 H), 6.76 (s, 1 H), 4.56 (br s, 1 H), 4.31-4.19 (m,
1 H), 3.93 (dd, 2.1),), =12 Hz, , = 3.9 Hz, 1 H), 3.64-3.61 (m, 4 H), 3.76-3.69 (m, 1 H),
3.56 (dd, 2.1),), = 11 Hz, 3.1),), = 3.2 Hz, 1 H), 3.46-3.36 (m, 3 H), 3.23-3.13 (m, 1 H), 1.50
(br s, 6 H), 1.23 (d, 3.1),), = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)280): 6 — 114.6-
(— 115.5) (m, 2 F); MS (MALDI): m/z = 436.0 ([M+H]+).
2015/076192
Example 46: 4- difluorometh | 4- 3R methox meth | mor holin | 3R
i39 i68 46
According to general procedure 1, compound 46 is obtained from ng materials i39
and i68 in 67% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.77 (t, 2JHf = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.67 (brs, 2 H), 4.44-4.24 (m,
2 H), .83 (m, 3 H), 3.75-3.63 (m, 2 H), 3.60-3.36 (m, 5 H), 3.31 (s, 3 H), 3.21-3.04
(m, 2 H), 1.23 (d, 3.1,”, = 6.7 Hz, 3 H); 19F NMR (376 MHz, 80): 5 — 115.0 (br s, 2 F);
MS (MALDI): m/z = 452.3 ([M+H]+).
i36 i68 47
According to general procedure 1, compound 47 is obtained from starting materials i36
and i68 in 85% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.86 (s, 1 H),
7.72 (t, 2JHf = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.75 (s, 1 H), 4.64 (br s, 1 H), 4.53-4.42 (m,
2 H), 4.37-4.25 (m, 1 H), 4.05-3.96 (m, 4 H), 3.92-3.84 (m, 1 H), 3.77-3.66 (m, 5 H), 3.60-
3.52 (m, 1 H), 3.44-3.35 (m, 1 H), 3.22-3.10 (m, 1 H), 1.23 (d, 3JH,H = 6.7 Hz, 3 H);
19F NMR (376 MHz, (CD3)ZSO): 8 — 114.9—(— 117.1) (m, 2 F); MS (MALDI): m/z = 450.0
([M+H]+)-
Example 48: 4S 5R 4- 2-amino difluorometh | n lmor holino—1 3 5-
triazin l h drox meth |meth l-oxazolidinone 48
o ,0
L l l l
N AOTBS N
F F l. ,L
l N “”“N HN/I: FLY}: N N [OH
A A + L b ~~~~~~~~~~~~~~~~~ A l
3%.wa "c: -0 /,
N. o [I]; A] N N’ \r“
(Boc)2N” O
N HzN' N o“
i74 i73 48
tert—Butyl N-tert—butoxycarbonyl-N-(5-(4-chloromorpholino-1,3,5-triazinyl)—4-
(difluoromethyl)pyrimidinyl)carbamate (i74, 350 mg, 643 umol, 1.0 eq.), (4S,5R)—4-
(((tert—butyldimethylsilyl)oxy)methyl)—5-methyloxazolidinone (i73, 174 mg, 709 umol,
1.1 eq.), 4,5-bis(diphenylphosphino)—9,9-dimethylxanthene (22.3 mg, 38.5 umol, 0.06 eq.),
cesium carbonate (419 mg, 1.29 mmol, 2.0 eq.) and palladium(ll) acetate (5.80 mg,
.8 umol, 0.04 eq.) are mixed in 1,4-dioxane (5 mL) under en atmosphere and
heated at 95 °C for 2 hours. After this time, the reaction mixture is allowed to cool down to
room temperature, zed H20 is added, and the aqueous layer is separated and
ted with ethyl e (3 x). The combined organic layer is dried over ous
sodium sulfate, filtered and the solvent is evaporated under reduced pressure.
The above residue is dissolved in tetrahydrofuran (5 mL) and aqueous HCI (3M, 2.00 mL,
6.00 mmol, 14 eq.) is added. The resulting mixture is heated at 60 °C overnight. Then,
aqueous saturated sodium bicarbonate and ethyl acetate are added. The aqueous layer is
separated and extracted with ethyl acetate (3 x). The combined organic layer is dried over
anhydrous sodium sulfate, filtered and concentrated und d pressure. Purification by
column chromatography on silica gel (100 % ethyl acetate) gives product 48 as a
colorless solid (55% yield).
1H NMR (400 MHz, (CD3)ZSO): 8 9.23 (s, 1 H), 8.23 (t, 2JH,F = 54 Hz, 1 H), 7.81-7.53 (m,
2 H), 4.99 (t, 2JH,F = 5.2 Hz, 1 H), 4.82 (q, 2JH,F = 6.5 Hz, 1 H), 4.56-4.51 (m, 1 H), 4.03-
3.97 (m, 1 H), 3.95-3.60 (m, 9 H), 1.50 (d, ZJHf = 6.5 Hz, 3 H); 19F NMR (376 MHz,
(CD3)ZSO): 8 — 121.3 (s, 1 F), — 121.4 (s, 1 F); MS (MALDI): m/z = 439.1 ([M+H]+).
Example 49: 4S 5R 6- 2-amino rometh l rimidin l mor holino-
,0. .10
L, ,1 LAN A
F. A: «Al FAA/.F I N
T ..\ f Q [ l A F F
t, /,l
x l N' ”N AOTBDPS “Y N. N WOH
BA ,B\ A
l N 0
A... 1 w l ll
+ / I L t I
A l A
A l Br” \V ‘N‘””\_ N \V N” \,
N ”N(Boc)2 N’ N(Boc)2 l A, .1- AL A, /
l o‘ '0 H2N N 0
W1 W8 49
tert—Butyl N-[5-bromo(difluoromethyl)pyrimidinyl]-N-ten‘-butoxycarbonyl-
carbamate (i71, 44.0 mg, 104 umol, 1.0 eq.), bis(pinacolato)diboron (27.0 g, 106 umol,
1.0 eq.), KOAc (31.0 mg, 316 umol, 3.0 eq.) and [1,1’-bis(diphenylphosphino)ferrocene]—
dichloropalladium(|l) (7.70 mg, 10.5 umol, 0.10 eq.) are mixed in 1,4-dioxane (2 mL) under
nitrogen atmosphere and heated at 95 °C for 55 minutes.
After this time, the above reaction mixture is allowed to cool down to room temperature.
Then, compound i78 (64.0 mg, 105 umol, 1.0 eq.), potassium phosphate
tribasic (44.0 mg, 207 umol, 2.0 eq.), chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-
1,1’-biphenyl) [2-(2’-amino-1,1’-bipheny|)]-pa||adium(|l) (Sigma-Aldrich, product number
741825, 8.20 mg, 10.4 umol, 0.10 eq.), 1,4-dioxane (2 mL) and deionized H20 (0.5 mL)
are added and the resulting dark mixture is placed in a pre-heated oil bath at 95 °C for
16 hours. After this time, aqueous saturated sodium bicarbonate and dichloromethane are
added. The aqueous layer is separated and extracted with dichloromethane (3 x). The
combined organic layer is dried over anhydrous sodium e, filtered and concentrated
under d pressure. This intermediate is purified by column chromatography on silica
gel (cyclohexane / ethyl acetate 1:0 9 1:1) to afford a colorless semisolid.
The semisolid ed above is then dissolved in tetrahydrofuran (2 mL) and a solution of
HCI in dioxane (1 M, 100 uL, 100 umol, 1.0 eq) is added. The resulting mixture is stirred at
room temperature overnight. After this time, the solvents are evaporated and the residue
is dried in vacuo.
The above salt is then dissolved in tetrahydrofuran (2 mL) and a solution of
tetrabutylammonium fluoride hydrate in tetrahydrofuran (1 M, 100 uL, 100 umol, 1.0 eq.) is
added. The reaction mixture is allowed to stir at room temperature for 2 days. After this
time, aqueous saturated sodium bicarbonate is added and the product is extracted with
ethyl acetate (3 x). The combined organic layer is washed with an aqueous ted
NH4CI-solution (3 x), dried over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to afford a ish solid. This solid is triturated with diethyl ether (5 x)
and dried in vacuo. The d t 49 is ed as a ess solid (5.5 % yield).
1H NMR (400 MHz, CD30D): 58.64 (s, 1 H), 7.69 (s, 1 H), 7.15 (t, 2JH,F = 54 Hz, 1 H),
4.82-4.76 (m, 1 H), 4.66-4.61 (m, 1 H), 4.17 (dd, 2JH,H =12 Hz, 3JH,H= 4.1 Hz, 1 H),
3.78 (dd, 2.1.”, = 12 Hz, 3.1.”, = 1.5 Hz, 1 H), 3.72-3.61 (m, 8 H), 1.61 (d, 3.1.”, = 6.6 Hz,
3 H); 19F NMR (376 MHz, CD30D): 5— 121.4 (s, 1 F), — 121.5 (s, 1 F); MS ):
m/z = 438.4 ([M+H]+).
Example 50: 4- difluorometh | 4- 3R meth lmor holin | 3-oxa
azabic clo 3.1.1 he tan |-1 3 5-triazin | ridinamine 50
1 wk ”ng0 J
a. f N/J\
N5; N yoga J11} F F
N JN’N ‘ /
,ng U + T! AL vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvp i Ii 1
1 l“N/ “N Cl “NV ‘N (”PM “N” N
(5 ""23 ii / Q J F J
x" “I? ’ \f’ “‘ N“
i40 i68 50
According to general procedure 1, compound 50 is obtained from starting materials MO
and i68 in 52% yield as a colorless solid. 1H NMR (400 MHz, SO): 8 8.90 (s, 1 H),
7.82 (t, 2JHf = 55 Hz, 1 H), 6.87 (br s, 2 H), 6.76 (s, 1 H), 4.55-4.51 (m, 1 H), .14 (m,
3 H), 4.12-4.25 (m, 2 H), 3.92-3.80 (m, 1 H), 3.76-3.68 (m, 3 H), 3.55-3.51 (m, 1 H),
3.38 (m, 1 H), 3.20-3.13 (m, 1 H), 2.68 (m, 1 H), 1.78 (m, 1 H), 1.20 (d, 3JH,H = 6.9 Hz,
3 H); 19F NMR (376 MHz, (CD3)280): 8 — 115.0 (br s, 2 F); MS (MALDI): m/z = 420.6
([M+H]+)-
M1 i68 51
ing to general ure 1, compound 51 is obtained from starting materials M1
and i68 in 36% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.99 (s, 1 H),
7.89 (t, 2JHf = 55 Hz, 1 H), 6.84 (brs, 2 H), 6.77 (s, 1 H), 4.69 (m, 3 H), 4.37 (m, 1 H),
3.91-3.85 (m, 3 H), 3.75-3.53 (m, 4 H), 3.42-3.35 (m, 1 H), 3.22-3.15 (m, 1 H), 3.12-3.08
(m, 1 H), 1.85 (m, 1 H), 1.24 (d, 3.1,”, = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)280): 5
— 116.0 (br s, 2 F); MS (MALDI): m/z = 420.6 ([M+H]+).
Example 52: 4- rometh | 4- 3R meth lmor holin | 1R4R oxa
azabic clo 2.2.1 he tan |-1 3 5-triazin | ridinamine 52
,0 0
ENE\ E
XXL? 1:ng k
N 0' N .10 ~ (1,,
i42 i68 52
According to general procedure 1, compound 52 is obtained from ng materials i42
and i68 in 44% yield as a colorless solid (1 :1 mixture of rotamers). 1H NMR (400 MHz,
(CD3)ZSO): 8 8.89 (m, 1 H), 7.77 (m, 1 H), 6.84 (brs, 2 H), 6.76 (s, 1 H), 5.02-4.97 (m,
1 H), 4.68-4.66 (m, 2 H), 4.31 (m, 1 H), 3.89-3.85 (m, 1 H), 3.79-3.57 (m, 3 H), 3.57-3.44
(m, 4 H), 3.22 (m, 1 H), 1.90-1.83 (m, 2 H), 1.21 (d, 3.1,”, = 6.9 Hz, 3 H); 19F NMR
(376 MHz, (CD3)ZSO): 8 — 115.5 (br s, 2 F); MS ): m/z = 420.2 ([M+H]+).
Example 53: 4- difluorometh l 4- 3R meth lmor holin l 18 4S oxa
azabic clo 2.2.1 he tan l-1 3 5-triazin l ridinamine 53
0,, o
t E
\i F“). F
\ 2‘0 kMN
E, 7‘ E i
, x £3, F F
O x, \ 65’\‘
W“““““—*
A. [fix (I? E -/] r j? E
\N 7
N ‘N CI N N N” \
., [\‘j “V “N NHz
i43 i68 53
According to general procedure 1, compound 53 is obtained from ng materials M3
and i68 in 53% yield as a colorless solid (1 :1 mixture of rs). 1H NMR (400 MHz,
SO): 8 8.90 (m, 1 H), 7.77 (m, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 5.02-4.96 (m,
1 H), 4.68-4.62 (m, 2 H), 3.90 (m, 1 H), 3.80 (m, 1 H), 3.70 (m, 2 H), 3.57 (m, 2 H),
3.45 (m, 3 H), 3.20 (m, 1 H), 1.90-1.83 (m, 2 H), 1.21 (d, 3.1,”, = 6.9 Hz, 3 H); 19F NMR
(376 MHz, (CD3)ZSO): 8 — 115.0 (br s, 2 F); MS (MALDI): m/z = 420.2 ([M+H]+).
Example 54: 5- 4 6-bis 3R eth lmor holin l-1 3 5-triazin l
(difluoromethyl)pyridinamine (54)
o /.O.\
[ Yk \LQ RT} EMTK
,3 N1 + 1
m, 11
.1 »»»»»»»». .
111?... A. J
MMMMMMM EN/LNHZ
i8 i68 54
According to general procedure 1, compound 54 is obtained from ng materials i8 and
i68 in 61% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H), 7.77
(t, 2JHf = 55 Hz,1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.47 (m, 4 H), 3.89-3.81 (m, 4 H),
3.51-3.34 (m, 4 H), 3.12 (m, 2 H), 1.71 (m, 4 H), 0.86 (m, 6 H). 19F NMR (376 MHz,
(CD3)ZSO): 8 - 115.0 (br s, 2 F); MS (MALDI): m/z = 450.3 ([M+H]+).
Example 55: 5- 4 6-bis 8-oxaazas iro 3.5 5- l -1 3 5-triazin l
oromethyl)pyridinamine(55)
(.0.1 )0.
1, 1 1/
fi‘\w:\ 2}”? FRl/F hi 1,»:
Fa“, [F
“'1,” 4.
> N4; 5N
1 * O/Bxxfxmifiy
------------------------~>
. 1. :l .l 1,1
,,,, \NM \N xN NN 'CN/ N
‘C’ {/3333
A . 11. 71 l
V 1E1 N‘ NH;
i9 i68 55
According to general procedure 1, compound 55 is obtained from starting materials i9 and
i68 in 59% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.74 (s, 1 H), 7.65
(t, 2JHf = 55 Hz, 1 H), 6.81 (br s, 2 H), 6.75 (s, 1 H), 3.68 (m, 8 H), 3.49 (m, 4 H), 2.46-2.38
(m, 4 H), 2.25-2.16 (m, 4 H), 1.72-1.66 (m, 4 H); 19F NMR (376 MHz, (CD3)ZSO): 8 — 115.5
(br s, 2 F); MS (MALDI): m/z = 474.3 ([M+H]+).
oromethyl)pyridinamine(56)
(ck f,.o\
N” "“ Mfg/\N / ‘\ / F». ,xF
+ \O/B-M‘Hfi/xfi‘] 5‘14ka —>
, 1. 11. ,
f ’11
N ”"N C: “‘N‘” “N f" "N N El “1 O\ //“} U8 /’ O.......J ..........
V N N NH2
i10 i68 56
According to general procedure 1, compound 56 is obtained from ng materials HO
and i68 in 59% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.76 (t, 2JHf = 55 Hz, 1 H), 6.82 (br s, 2 H), 6.76 (s, 1 H), 4.50 (m, 2 H), 4.29 (m, 2 H),
4.02-3.84 (m, 4 H), 3.40 (m, 4 H), 3.08 (m, 2 H), 2.34 (m, 2 H), 1.02 (m, 6 H), 0.77 (m,
6 H); 19F NMR (376 MHz, (CD3)280): 5 — 115.0 (brs, 2 F); MS (MALDI): m/z = 478.4
QM+HTl
i44 i68 57
ing to general procedure 1, compound 57 is obtained from starting materials M4
and i68 in 45% yield as a colorless solid (1 :1 e of rotamers). 1H NMR (400 MHz,
(CD3)280): 8 8.87 (m, 1 H), 7.77 (m, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.71-4.35 (m,
4 H), 3.92 (m, 1 H), 3.72 (m, 1 H), 3.56 (m, 1 H), 3.42 (m, 1 H), 3.23-3.18 (m, 4 H),
1.24 (m, 3 H); 19F NMR (376 MHz, (CD3)280): 5 - 69, — 115.0 (brs, 2 F); MS (MALDI): m/z
= 435.1 ([M+H]+).
/05 cm
L k x): F. .F l~
x .
N \>/ {‘3 T l? "\
Yd»? \O 13 U/W;
iiiiiii,
F //////\ / F a “£142“: RT F
\ '\, '\ "m 5 K
_.,/
13/? is N Cl N hi1? N
F )1 a P
F E
\ ,r/ F //
1?] N NHZ
i45 i68 58
According to general procedure 1, compound 58 is obtained from starting materials M5
and i68 in 41% yield as a colorless solid (1 :1 mixture of rotamers). 1H NMR (400 MHz,
(CD3)280): 8 8.87 (m, 1 H), 8.07 (m, 1 H), 7.77 (m, 1 H), 6.86 (br s, 2 H), 6.76 (s, 1 H),
4.65-4.77 (m, 1 H), 4.36-4.01 (m, 3 H), 3.83 (m, 1 H), 3.62 (m, 1 H), 3.52 (m, 1 H), 3.35
(m, 1 H), 3.10 (m, 1 H), 1.18 (d, 3JH,H = 6.9 Hz, 3 H); MS (MALDI): m/z = 421.1 ([M+H]+).
MG i68 59
According to general procedure 1, nd 59 is obtained from starting materials MG
and i68 in 32% yield as a colorless solid (1 :1 mixture of rotamers). 1H NMR (400 MHz,
(CD3)ZSO): 6 8.89-8.84 (m, 1 H), 8.12-7.37 (m, 2 H), 6.81-6.75 (m, 3 H), 4.64 (m, 1 H),
4.30 (m, 1 H), 3.90 (m, 1 H), 3.72 (m, 1 H), 3.56 (m, 1 H), 3.39 (m, 2 H), 3.14 (m, 2 H),
1.20 (d, 3.1,”, = 6.9 Hz, 3 H), 1.04 (m, 1 H), 0.42 (m, 2 H), 0.22 (m, 2 H); 19F NMR
(376 MHz, (CD3)ZSO): 6 — 115.0 (br s, 2 F); MS (MALDI): m/z = 393.0 ([M+H]+).
i4? i68 60
According to general procedure 1, compound 60 is obtained from starting materials M7
and i68 in 41% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.96 (s, 1 H),
7.75 (t, 2JH,F = 55 Hz, 1 H), 7.07 (br s, 2 H), 6.80 (s, 1 H), .97 (m, 2 H), 4.78-4.54 (m,
1 H), 4.33 (m, 1 H), 3.91 (m, 1 H), 3.71 (m, 1 H), 3.57 (m, 1 H), 3.41 (m, 1 H), 3.29 (m,
1 H), 1.27 (d, 3.1,”, = 6.9 Hz, 3 H); 19F NMR (376 MHz, (003)280): 5 - 69, - 115.0 (brs,
2 F); MS (MALDI): m/z = 422.3 ([M+H]+).
Example 61: 5- 4- 2 2-difluoroethox 3R meth lmor 4- l-1 3 zin l-
4- difluorometh l ridinamine 61
(O\ O
N”]\ l
\ [
\. /L“Q FEF
WN no-6. W < 1:
A 41m !L U ,5 m
F . £6 I
i o 66w “or . 5 1
N “3% i 0” N
F \N/ F m
N WNNHZ
M8 i68 61
ing to general procedure 1, compound 61 is obtained from starting materials M8
and i68 in 60% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.95 (s, 1 H),
7.89 (t, 2JHf = 55 Hz, 1 H), 7.04 (br s, 2 H), 6.80 (s, 1 H), 6.37 (m, 1 H), 4.68-4.53 (m,
3 H), 4.25 (m, 1 H), 3.90 (m, 1 H), 3.70 (m, 1 H), 3.55 (m, 1 H), 3.41 (m, 1 H), 3.25 (m,
1 H), 1.26 (d, 3JH,H = 6.9 Hz, 3 H).;19F NMR (376 MHz, (003)280): 6 — 115.0 (br s, 2 F), -
126; MS (MALDI): m/z = 404.1 ([M+H]+).
e 62: 5-|4-|(3aR,6aS)—1,3,3a,4,6,6a-hexahydrofuro|3,4-clpyrrolyl||(3R)—3-
meth lmor holin l-1 3 5-triazin l difluorometh l ridinamine 62)
[ /<J\ “mL i=6 F { /5\
3 l i
WAN \OK , m N’P‘N F F
<1 6 0* N 'l N M
O “Ml-f IT] 0 ”/34 N NHZ
i49 i68 62
According to general procedure 1, compound 62 is obtained from starting materials i49
and i68 in 20% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.90 (s, 1 H),
7.86 (t, 2JH,F = 55 Hz, 1 H), 6.82 (br s, 2 H), 6.76 (s, 1 H), 4.67 (m, 1 H), 4.35 (m, 1 H),
3.93-3.43 (m, 14 H), 3.16 (m, 1 H), 2.99 (m, 2 H), 1.21 (d, 3JH,H = 6.9 Hz, 3 H); 19F NMR
(376 MHz, (CD3)ZSO): 8 — 115.0 (br s, 2 F); MS (MALDI): m/z = 435.2 ([M+H]+).
Example 63: 5- 4- 4aS 7aR -2 3 4a 5 7 7a-hexah dro- 1 4 dioxino 2 3-c - l
3R meth lmor holin l-1 3 5-triazin l difluorometh l ridinamine 63
i50 i68 63
According to general procedure 1, compound 63 is obtained from starting als i50
and i68 in 25% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.92 (s, 1 H),
7.88 (t, 2JHf = 55 Hz, 1 H), 6.84 (brs, 2 H), 6.76 (s, 1 H), 4.70 (m, 1 H), 4.36-4.26 (m,
3 H), 3.88 (m, 1 H), 3.79-3.53 (m, 12 H), 3.41 (m, 1 H), 3.09 (m, 1 H), 1.21 (d, 3JH,H =
6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)280): 8 — 115.0 (br s, 2 F); MS (MALDI): m/z =
451.2 ([M+H]+).
Example 64: 4- rometh l 4- 4 4-difluoro i erid l 3R meth lmor holin-
4- l-1 3 5-triazin l ridinamine 64
o\ .,_,o\
LN k \::;L? F]? i k
/: ,
0 MIBM/4% / Fx F
NfiiNfiiC, +
«m» H[l
FmF; i ‘
Ki?, F FL‘ J l
XN J’Nfiz
i51 i68 64
According to general procedure 1, compound 64 is obtained from ng materials i51
and i68 in 61% yield as a ess solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.88 (s, 1 H),
7.74 (t, 2JHf = 55 Hz, 1 H), 6.85 (brs, 2 H), 6.77 (s,1 H), 4.70 (m, 1 H), 4.32 (m, 1 H),
3.99 (m, 5 H), 3.72 (m, 1 H), 3.56 (m, 1 H), 3.41 (m, 1 H), 3.18 (m, 1 H), 2.01 (m, 4 H),
1.21 (d, 3.1,”, = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)280): 5 - 95.5, - 115.0 (brs, 2 F);
MS (MALDI): m/z = 442.0 ([M+H]+).
{ 13‘ N (3‘ N {a J/,.~\,,31/ SIN, \U/ \Jj
at.” V N 0'4 \ N NHz
i52 i68 65
According to general procedure 1, compound 65 is obtained from starting materials i52
and i68 in 49% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.86 (s, 1 H),
7.75 (t, 2JHf = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.65 (m, 1 H), 4.35 (m, 5 H),
3.87 (m, 1 H), 3.70 (m, 5 H), 3.57 (m, 1 H), 3.43 (m, 1 H), 3.16 (m, 1 H), 1.79 (m, 4 H),
1.20 (d, 31,1, = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)280): 5 — 115.5 (br s, 2 F); MS
(MALDI): m/z = 449.3 ([M+H]+).
1,011.1 ‘
I .1
.1 :1, F F
1 , A
1 :71?“ {g 1 If
.1?» .1/ F F
11‘ 0/ 1.“? /% {ix
1 11 1 1., 1 —* l 1?. J
1 l?! N C! N 1111 1 N N
O Ox/K 11 \1
“V“ \ 311/ N/ \NHQ
i55 i68 66
According to l procedure 1, compound 66 is obtained from ng materials i55
and i68 in 61% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.77 (t, 2JHf = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.46 (m, 2 H), 3.81-3.77 (m,
6 H), 3.55 (m, 2 H), 3.44 (m, 2 H), 1.49 (s, 6 H), 1.28 (d, 3JH,H = 6.9 Hz, 6 H); 19F NMR
(376 MHz, (CD3)280): 8 — 115.0 (br s, 2 F); MS (MALDI): m/z = 450.4 ([M+H]+).
[01 1 1
1. ,0.1
~1N/
1 \ £11-? F111,? N
o 0 F 1':
. N431“: N511!“
,l... 0 »...
1.11 + 1 .1 1* ,1, 11
,1. L1
1 1?. N Cl N $11 r N
I T ‘H
O 1
\ :11/ O1.“ 1N4 NNHZ
i56 i68 67
According to general procedure 1, compound 67 is obtained from starting materials i56
and i68 in 37% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.84 (s, 1 H),
7.89 (t, 2JHf = 55 Hz, 1 H), 6.85 (brs, 2 H), 6.76 (s,1 H), 4.60 (m, 1 H), 4.31 (m, 1 H),
3.92 (m, 2 H), 3.83 (m, 4 H), 3.65 (m, 1 H), 3.51-3.41 (m, 5 H), 3.28 (s, 3 H), 3.12 (m,
1 H), 1.49 (s, 3 H), 1.48 (s, 3 H); 19F NMR (376 MHz, (CD3)280): 8 — 115.5 (brs, 2 F); MS
(MALDI): m/z = 466.4 ([M+H]+).
Example 68: 3R 4- 6-amino difluorometh l rid l 3 3-dimeth lmor holin
yl)-1,3,5-triazinyl|morpholinyl|methanol (68)
/O~_. /0
HO {El ~~~~~~~~;/L(; FLF HO 1:1? 1;: F
x, 0’ “1;?
» 151;)
a f: 1:3? (SN/J RNA NH?
i57 i68 68
According to general procedure 1, compound 68 is obtained from starting materials i57
and i68 in 58% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.83 (s, 1 H),
7.77 (m, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.91 (m, 1 H), 4.35 (m, 2 H), 4.05 (m, 1 H),
3.97-3.70 (m, 6 H), 3.54-3.38 (m, 5 H), 3.12 (m, 1 H), 1.49 (s, 3 H), 1.48 (s, 3 H); 19F NMR
(376 MHz, (CD3)ZSO): 8 — 115.5 (br s, 2 F); MS (MALDI): m/z = 453.2 ([M+H]+).
Example 69: 4- difluorometh l 4- 3 3-dimeth lmor holin l 3 7-dioxa
azabic clo 3.3.1 9- l-1 3 zin l ridinamine 69
[0 0
l § l
I? \ )JMO Paw/F “N “m
“71 l l l
/ it
N N x O B ”/55“; N \ N F‘K x. F
KN.» + i 1 —~«—» )1 ,1
Cl N \ L
I N «N
“T,N N, ______ x}
ii , x / )1 ,
If» A
0 fl) .. / x
. o z
x/ N j/j N NH;
O l o
i54 i68 69
According to general procedure 1, compound 69 is obtained from starting materials i54
and i68 in 57% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.83 (s, 1 H),
7.69 (t, 2JHf = 55 Hz, 1 H), 6.85 (br s, 2 H), 6.76 (s, 1 H), 4.47-4.37 (m, 2 H), 4.01 (m,
4 H), 3.80-3.71 (m, 8 H), 3.45 (m, 2 H), 1.48 (s, 6 H); 19F NMR (376 MHz, (CD3)ZSO):
8 — 115.7 (br s, 2 F); MS (MALDI): m/z = 464.3 +).
e 70: 5- 4- 4-c clo ro l i erazin l 3 3-dimeth lmor holin l -1 3 5-
triazin l difluorometh l ridinamine 70
0 xx
{HAIL/N \ i g
F‘x ,F 1/
“Q N
WAN V0 ‘3 L N}. a,,,,,, F
,LQ 31 t [(41% ---------------- w ,1. at,
r N N c: N N r” AN N U :1
7,14.» RN ,,,,, NW
v7 RN N92
i58 i68 70
According to general procedure 1, compound 70 is obtained from starting materials i58
and i68 in 12% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.82 (s, 1 H),
7.72 (t, 2JHf = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 3.82 (m, 4 H), 3.71 (m, 4 H),
3.44 (m, 2 H), 2.58 (m, 4 H), 1.64 (m, 1 H), 1.44 (s, 6 H), 0.45 (m, 2 H), 0.36 (m, 2 H);
19F NMR (376 MHz, (003)280): 5 — 115.4 (br s, 2 F); MS (MALDI): m/z = 460.4 ([M+H]+).
o\ o
[ M;;i\(‘) 1
x /L\\\\\ F F /£§
“\sz N N
NAN / L
0.8..kvx.,§\ l.
N/AN F F
\ ix 1’1‘\ L /?L i
,,,,,,, 31 l
f N N c: N“ ‘N f “N1 /
11 «
~ .N. U. N. J J
4 x
o W ‘4 h?! o , V N NH2
i59 i68 71
According to general procedure 1, compound 71 is obtained from starting als i59
and i68 in 42% yield as a colorless solid. 1H NMR (400 MHz, SO): 8 8.82 (s, 1 H),
7.73 (t, 2JHf = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 3.88-3.69 (m, 10 H), 3.47-
3.44 (m, 4 H), 3.24 (m, 3 H), 2.52-2.45 (m, 4 H), 1.44 (s, 6 H); 19F NMR (376 MHz,
(CD3)ZSO): 6 — 115.4 (br s, 2 F); MS (MALDI): m/z = 478.4 ([M+H]+).
Example 72: 4- difluorometh l 4- 3 3-dimeth lmor holin-4
1 3 5-triazin l 2-amine 72
WC K0
\N ‘\>LQ FM} L: \N
i “x
, B
4"“,L
.2 F. ,1:
CC N N O 4» N” N
L. H * l J”N ©ij —-~ )6, EL l
o/ \N/ Cl N” “N o" "N
1.: ll 1
135/ N” ”“NHZ
i60 i68 72
According to general procedure 1, compound 72 is ed from starting materials i60
and i68 in 41% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.86 (s, 1 H),
7.73 (t, 2JHf = 55 Hz, 1 H), 7.02 (br s, 2 H), 6.78 (s, 1 H), 5.62 (m, 1 H), 4.90 (m, 2 H),
4.63 (m, 2 H), 3.85 (m, 4 H), 3.49 (m, 2 H), 3.13 (s, 6 H); 19F NMR (376 MHz, (CD3)ZSO):
8 — 115.7 (br s, 2 F); MS (MALDI): m/z = 409.3 +).
Example 73: 4- difluorometh l 4- 3 3-dimeth lmor holin l 3S -tetrah drofuran-
3- lox -1 3 5-triazin l ridinamine 73
(o ) A1
L L L...;>Lwo.
éfix ,«(.«L"\\ ,B LL”
0 0 ,1 {‘3 O 6;“ , FL X/F
«VJ. "i it + TL , ,1. L L L
o N cu N N 01 ,N ng
LL 1; l
Ix]: \N/ ‘NHg
i61 i68 73
According to general procedure 1, nd 73 is obtained from starting materials i61
and i68 in 44% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.76 (t, 2JHf = 55 Hz, 1 H), 6.99 (br s, 2 H), 6.78 (s, 1 H), 5.48 (m, 1 H), 3.84-3.73 (m,
8 H), 3.49 (m, 2 H), 2.21 (m, 1 H), 2.05 (m, 1 H), 1.52 (s, 3 H). 1.51 (s, 3 H);19F NMR
(376 MHz, (CD3)280): 8 — 115.7 (br s, 2 F); MS (MALDI): m/z = 423.3 ([M+H]+).
e 74: 4- difluorometh l 4- 3 3-dimeth lmor holin l 3R -tetrah drofuran-
3- lox -1 3 5-triazin l ridinamine 74
(omI / ,L IOl/
LLN/ \ xxx/31“»? FLY/F LN
/ “x
/O~\_ OLBL /«N
N”? L
N Nix} o\k
N“ N FLY, F
'35 l I] +
\ M /E <\ 1 EL
““0“ Q"N“"'ol ‘N’A‘N A
0 “N ’8 :“\
Li . L L l.
bi: ‘N “NHL
i62 i68 74
According to l procedure 1, compound 74 is obtained from starting materials i62
and i68 in 37% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.76 (t, 2JHf = 55 Hz, 1 H), 6.99 (br s, 2 H), 6.78 (s, 1 H), 5.48 (m, 1 H), 3.84-3.73 (m,
8 H), 3.49 (m, 2 H), 2.21 (m, 1 H), 2.05 (m, 1 H), 1.52 (s, 3 H). 1.51 (s, 3 H);19F NMR
(376 MHz, (CD3)280): 8 — 115.6 (br s, 2 F); MS (MALDI): m/z = 423.3 ([M+H]+).
Example 75: 4- rometh l 4- 3 3-dimeth lmor holin l tetrah dro ran
lox -1 3 5-triazin l ridinamine 75
0L 0.“
L 14/
N” NILO FLT/F ILLN/lf
my F F
o NA :54‘OLéw Li \
0 NLLLN
l l L L ’* El“ Ml W L L L L i
w’ 0 N Cl N’ “d x O N xii] xi
“"‘N/ “N "‘NHZ
i63 i68 75
According to general procedure 1, compound 75 is obtained from starting materials i63
and i68 in 61% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.87 (s, 1 H),
7.76 (t, 2JHf = 55 Hz, 1 H), 6.99 (br s, 2 H), 6.78 (s, 1 H), 5.15 (m, 1 H), 3.82 (m, 6 H),
3.48 (m, 4 H), 2.07-2.00 (m, 2 H), 1.74 (m, 2 H), 1.51 (s, 6 H); 19F NMR (376 MHz,
(CD3)ZSO): 8 — 115.7 (br s, 2 F); MS (MALDI): m/z = 437.4 ([M+H]+).
Example 76: 4- rometh l 4- 3 3-dimeth lmor holin l 1 1-dioxo-1 4-
thiazinan l-1 3 5-triazin l ridinamine 76
Q 0,: 1 O7
/' ’K/(
. N), F,» :i . .
N? ”N 1 03» *1: N 1%
+ 11 i \f /, N/‘iQN‘jMCl —>
N “Nix, ,
l N
l N “I f L E
02§k U / Ow§x¢ N “NH
3 “'1“ 2
i64 “58 76
According to general procedure 1, compound 76 is obtained from starting materials i64
and i68 in 56% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.83 (s, 1 H),
7.68 (t, 2JH,F = 55 Hz, 1 H), 6.88 (br s, 2 H), 6.77 (s,1 H), 4.19 (m, 4 H), 3.83 (m, 4 H),
3.47 (m, 2 H), 3.22 (m, 4 H), 1.52 (s, 6 H); 19F NMR (376 MHz, (003)280): 5 — 115.3 (br s,
2 F); MS (MALDI): m/z = 470.2 ([M+H]+).
i53 i68 77
ing to general procedure 1, nd 77 is obtained from starting materials i53
and i68 in 31% yield as a colorless solid. 1H NMR (400 MHz, (CD3)ZSO): 8 8.88 (s, 1 H),
7.78 (t, 2JHf = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.96 (m, 1 H), 4.73 (m, 1 H),
.24 (m, 3 H), 4.05 (m, 1 H), 3.90 (m, 2 H), 3.72 (m, 2 H), 3.59 (m, 1 H), 3.51-
3.36 (m, 4 H), 3.23-3.02 (m, 2 H), 1.23 (d, 3.1,“, = 6.9 Hz, 3 H); MS (MALDI): m/z = 438.3
([M+H]+)-
WO 75130
ln-cell Western Blot
A2058 cells are plated at 20,000 cells/well in a 96-well plate (Perkin Elmer, Cat. No.
6005558) and 24 hours later treated with different compounds for 1 hour. For each
nd 7 different concentrations are applied on cells (5 uM, 1.25 uM, 0.625 uM,
0.3125 uM, 0.155 uM, 0.08 uM and 0.04 uM). Cells are fixed with 4% paraformaldehyde
for 30 minutes at room temperature, washed 2 times with 1% BSA in PBS, permeabilized
with 0.1% Triton X-100 in PBS/1% BSA for 30 minutes at room temperature and blocked
with 5% goat serum in PBS/1% BSA/0.1% Triton X-100 for 30 minutes at room
temperature. Cells are stained with primary antibody either with rabbit anti-pPKB S473
(1 :500; Cell Signaling Technology, Cat. No. 4058) ed with mouse anti-d-tubulin
(1 :2000; used for normalization; Sigma, Cat. No. T9026) or with rabbit anti-pS6
S235/S236 (1:500; Cell Signalling Technology, Cat. No.4856) combined with mouse anti-
lin (1 :2000; used for normalization) over night at 4 °C. After 3 times 5 minutes wash
with PBS/1% BSA/0.1% triton cells are treated with the secondary antibodies goat-anti-
mouse 80 (LICOR, Cat. No. 926-68070) and goat-anti-rabbit |RDye800 (LICOR,
926-32211) (each diluted 1:500 in PBS/1% BSA/0.1% triton) for 1 hour while shaking in
the dark. Cells are washed 3 times 5 minutes with PBS/1% BSA/0.1% triton and plate
scanned with the Odyssey Infrared Scanning system using both 700 and 800 nm
channels. As control for 0% inhibition vehicle (0.2% DMSO) is added to cells. To correct
for background staining in the data analysis wells are d only with secondary
antibodies.
For data analysis the mean background signal from channel 700 nm and 800 nm are
subtracted from each signal in l 700 nm and 800 nm, respectively. The signals in
each channel are normalized to the 0% inhibition and then signal ratio 800 nm over
700 nm is performed to obtain the values for either pPKB S473 or p86 S235/S236
normalized to d-Tubulin.
|C50 values of each compound are ined by plotting the ized pPBK S473 and
p86 S235/S236 signals, respectively, versus the compound concentrations (in logarithmic
scale) and then by fitting a sigmoidal dose-response curve with variable slope to the data
using GraphPadTM Prism.
Table 1: Comparative biological ties
This invention This invention W02010/052569
W02010/052569
Compound 1 Compound 2
,,o_ 0
[01 50,
T T (N)
N N
F F
F F
N \N N"’L:N FREE lAN N/KN FWF
A 4% 21 //\i\ (\N N/ [ Nr'L
0 \N
N [,A_
I 9%)] N [’ N"/"["‘NH2 0d 1 NAM—'2 [TN
(g [T
N/ NHZ T["r\1""[\‘NH2
pPKB
S473 IC50 108 149 34 64
8235/236 196 340 80 650
|C50 [nM]
Table 2: Comparative ical activities
This invention This ion W02010/052569
W02010/052569
Compound 6 Compound 7
o 505 O 50“.,
U T T E 1,, T T ,1
315i TiT 5 T T“T T
N N \ /“N/ “NO if“) N N \N N Na» «N
0d [ [
N/ ([3\ /j LN [\NH; 0y
NH2 N/ NH2 (Ev/I ELN‘I/\NH2
pPKB
S473 IC50 155 255 59 118
8235/236 215 433 97 224
[C50 [nM]
Table 3: Comparative biological activities
This invention This invention W02010/052569
W02010/052569
Compound 8 Compound 9
0 ,OK 0 ,0\
[NT TNT [ij TNT
N/kN F F N/LKN FKF F nil/KN F F [Ii/L33 FMS/F
of)N N \ ,x, N A, fN N N l/ N N N
I [ N/)\NH2 ’
N/ M‘N‘J 0d O
NH2 (ZN/1 EN“ J\NHg
pPKB
S473 IC50 74 196 35 91
8235/236 68 90 72 164
|C50 [n M]
Table 4: Comparative biological activities
This ion This invention W02010052569
WO20 005 5691 2
Compound 12 Compound 13
H H H H
N N EN N
[N1 [N1 1N1
F F
N \N “(/1th NgN F NALN [Kg/F
1 /"\N"R~N“*i\/"<>F\‘Ff’F (\N N/ \ flu/[M \N
1N/ <12 11 oy 1 \N/_.1:\N;.\ 4,,ng
0y AN 1 1
V [LN-4.1.12
pPKB
S473 IC50 208 302 43 116
8235/236 515 743 150 416
|C50 [nM]
Table 5: Comparative biological ties
This invention This invention WO2007/084786
Compound 16 Compound 17
,oN fox
1 “
Min {—17,}:
11:1” 0“ 11 5171' 1:11”
pPKB
S473 IC50 207 263 90 194
8235/236 184 277 149 384
|C50 [nM]
Table 6: Comparative biological activities
This invention This invention W02008/098058
WO 80582
Compound 18 Compound 19
[WOW 3,C>\:
pPKB
S473 IC50 243 555 78 175
8235/236 256 665 147 370
|C50 [nM]
Table 7: Comparative biological activities
This invention This invention WO2010052569
WO20 005 5691 2
Compound 20 Compound 21
(/0\ fix (/0\ {,o\
\l J l 1
N' ”'N' [NJ1 [My
)9, F\ F g F [T F J1; Pkg/VF (is, REF
l K‘ i,
l [N [ [
S "j [N‘LNHZ 8V"; S\/
g , /'
NHZ kN/l \NH2 S\ [\N/LNHz
pPKB
S473 IC50 146 311 57 343
8235/236 250 559 216 996
|C50 [nM]
Table 8: Comparative biological activities
This invention This invention WO2007/084786
Compound 25 Compound 26
1": £01 (“’1 1°:
N ‘u, N m, N u,” N ",0
F F
F F F F F F F
E N‘ \ E NI \ _ N‘ \ : Ni \
(\N N/ \ (\N N/ \ (\N N/ \N
1 [ [ N/JWH2 [AN N/ \N
OV‘ l
N/ 0 N/ 0d O
NH2 NH2 N/ NHz
pPKB
S473 [Gm 303 452 87 193
8235/236 294 553 191 617
|C50 [nM]
Table 9: Comparative ical activities
This invention This invention /084786
nd 27 Compound 28
£01 (01 1°) £01
N N N N
gNing F ‘N‘gNF F
(\N% gNl/gNr-FF NIXWFFF
Oi; / /
N \ fN \N (\N [ :N
0d 1 I
] N/J\NHZ 0Q
NH2 N/ 0d NAN“?
pPKB
S473 [Gm 614 883 77 290
8235/236 766 1100 146 1027
|C50 [nM]
Table 10: Comparative biological activities
This invention This ion WO2007/084786
Compound 23 Compound 24
’0» O O O
N N N N
F F
L a (F F F F F F F
N 2 V N \ N \ N \
/U‘N‘flflfi 0K;N 'N/ \
1 CgNAN/ \N N 'N/ \N
0‘7 “N“xNHz
N/ NHZ N/Jfiw2 Cg N/ NH2
pPKB
S473 |C50 285 564 84 340
8235/236 230 562 167 740
|C50 [nM]
Table 11: Comparative biological activities
This invention This invention WO2007/084786
Compound 31 Compound 32
0: £01 £01 (01
N N N N
F F
F F F F F F F F
E )NL\ ? NI \ § N. \ ? N| \
(\N N/ \ (\N N/ \ (\N N/ \N KN N/ \
O N/ 0
NH2 SN/ NH2 0Q {N/ Cd
NH2 [N/ NH2
pPKB
S473 |C50 146 248 100 191
8235/236 124 228 387 535
|C50 [nM]
Table 12: Comparative biological activities
This invention
Compound 48
O ”0-,
L A J
T F i
if if: 10“ 1
4&4“ N f0”
1T? NE; \,>“ 1?: I N \\;M
O \[X‘
HzN/A NV 0/ H2N” N/ “0/
S473 100 689
|C50 [nM]
P1100c
161 1864
IC50 [nM]
2015/076192
Table 13: Results of in-cell Western Blot
ln-cell Western blot
pPKB 8473 p86 8235/8236
Compound
IC50 [nM] IC50 [nM]
1 108 196
2 34 80
3 231 105
4 178 135
85 135
6 155 215
7 59 97
8 74 68
9 35 72
138 93
11 61 96
12 219 407
13 37 120
14 349.5 883
49 286
16 207 184
17 90 149
18 243 256
19 78 147
146 250
21 57 216
22 57 216
23 285 230
24 84 167
303 294
26 87 191
27 614 766
28 77 146
31 146 124
32 100 387
2015/076192
In-cell Western blot
pPKB 8473 p86 8235/8236
Compound
IC50 [nM] IC5O [nM]
207 229
36 99 153
37 533 268
38 219 79
39 106 47
40 252 160
41 436 261
42 54 45
43 383 154
44 197 87
45 234 93
46 956 426
47 469 176
48 100 nd
Claims (16)
1. A compound of formula (I), 5 wherein X1, X2 and X3 are, independently of each other, N or CH; with the o that at least two of X1, X2 and X3 are N; Y is N or CH; R1 and R2 are independently of each other 10 (i) a morpholinyl of a (II) R3 R4 (II) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1- 15 C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form er a bivalent residue – R5R6– selected from -CH2-O-CH2-, -CH2-NH-CH2-, or C1-C3alkylene optionally substituted with 1 to 4 F, or any of the structures wherein the arrows denote the bonds in formula (II); or 20 (ii) a saturated 5- to 6-membered heterocyclic ring Z containing 1 to 2 heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R9; wherein R9 is independently at each occurrence halogen, -OH, C1-C3alkyl, CH2OH, OH, CH2F, CHF2, CF3, CH2CF3, C1-C2alkoxy, lkoxyC1- C3alkyl, C3-C6cycloalkyl, =O, -NH2, NHCH3 or N(CH3)2; or two R9 substituents form 25 together a bivalent residue –R10R11– selected from -CH2-O-CH2-, -O-CH2CH2-O-, or C1-C3alkylene optionally substituted with 1 to 4 F; with the proviso that at least one of R1 and R2 is a morpholinyl of formula II; 17511707_1 ters) P42872NZ00 and tautomers, solvates and pharmaceutically acceptable salts thereof.
2. The nd of formula (I) according to claim 1, wherein X1, X2 and X3 are N; and tautomers, solvates and pharmaceutically acceptable salts thereof.
3. The compound of formula (I) according to claim 1 or claim 2, n said R1 and said R2 are independently of each other selected from 17511707_1 (GHMatters) P42872NZ00
4. The compound of formula (I) according to claim 3, wherein R1 and R2 are ndently of each other selected from 17511707_1 (GHMatters) P42872NZ00
5. The compound of formula (I) according to claim 1, wherein said compound is selected from 4-(difluoromethyl)(4,6-dimorpholino-1,3,5-triazinyl)pyridinamine; 4-(difluoromethyl)(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine; 5 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxaazabicyclo[3.2.1]octanyl)-1,3,5- triazinyl)(difluoromethyl)pyridinamine; 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)morpholino-1,3,5-triazinyl) (difluoromethyl)pyridinamine; 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)morpholino-1,3,5-triazinyl) 10 (difluoromethyl)pyrimidinamine; 5-(4,6-bis((S)methylmorpholino)-1,3,5-triazinyl)(difluoromethyl)pyridinamine; 5-(4,6-bis((S)methylmorpholino)-1,3,5-triazinyl)(difluoromethyl)pyrimidinamine; (S)(difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazinyl)pyridin amine; 15 (S)(difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazinyl)pyrimidin- 2-amine; 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)methylmorpholino)-1,3,5-triazinyl) oromethyl)pyridinamine; 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)methylmorpholino)-1,3,5-triazinyl) 20 (difluoromethyl)pyrimidinamine; 4-(difluoromethyl)(4-morpholino(piperazinyl)-1,3,5-triazinyl)pyridinamine; 4-(difluoromethyl)(4-morpholino(piperazinyl)-1,3,5-triazinyl)pyrimidinamine; (S)(difluoromethyl)(4-(3-methylmorpholino)(piperazinyl)-1,3,5-triazin yl)pyridinamine; 25 (difluoromethyl)(4-(3-methylmorpholino)(piperazinyl)-1,3,5-triazin yl)pyrimidinamine; 4-(difluoromethyl)(2,6-dimorpholinopyrimidinyl)pyridinamine; 4'-(difluoromethyl)-2,6-dimorpholino-[4,5'-bipyrimidin]-2'-amine; 4-(difluoromethyl)(4,6-dimorpholinopyrimidinyl)pyridinamine; 30 4'-(difluoromethyl)-4,6-dimorpholino-[2,5'-bipyrimidin]-2'-amine; luoromethyl)(4-morpholinothiomorpholino-1,3,5-triazinyl)pyridinamine; luoromethyl)(4-morpholinothiomorpholino-1,3,5-triazinyl)pyrimidinamine; 5-(6-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxaazabicyclo[3.2.1]octan yl)pyrimidinyl)(difluoromethyl)pyridinamine; 35 5-(2-(3-oxaazabicyclo[3.2.1]octanyl)morpholinopyrimidinyl) (difluoromethyl)pyridinamine; 17511707_1 (GHMatters) P42872NZ00 2-(3-oxaazabicyclo[3.2.1]octanyl)-4′-(difluoromethyl)morpholino-[4,5′-bipyrimidin]- 5-(2,6-bis((S)methylmorpholino)pyrimidinyl)(difluoromethyl)pyridinamine; 4'-(difluoromethyl)-2,6-bis((S)methylmorpholino)-[4,5'-bipyrimidin]-2'-amine; 5 (difluoromethyl)(6-(3-methylmorpholino)morpholinopyrimidinyl)pyridin amine; (S)-4'-(difluoromethyl)(3-methylmorpholino)morpholino-[4,5'-bipyrimidin]-2'-amine; 5-(4-(8-Oxaazabicyclo[3.2.1]octanyl)(8-oxaazabicyclo[3.2.1]octanyl)-1,3,5- triazinyl)(difluoromethyl)pyridinamine; 10 5-[4,6-bis(2,2-dimethylmorpholinyl)-1,3,5-triazinyl](difluoromethyl)pyridinamine; (S)(difluoromethyl)(2-(3-methylmorpholino)morpholinopyrimidinyl)pyridin amine; (S)-4'-(difluoromethyl)(3-methylmorpholino)morpholino-[4,5'-bipyrimidin]-2'-amine; 4-(difluoromethyl)[4-[(2S,6R)-2,6-dimethylmorpholinyl][(3R)methylmorpholin 15 yl]-1,3,5-triazinyl]pyridinamine; 5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridin- 2-amine; 4-[4-[6-amino(difluoromethyl)pyridyl]morpholino-1,3,5-triazinyl]morpholin one; 20 2-amino(difluoromethyl)pyrimidinyl]morpholino-1,3,5-triazinyl]morpholin one; 5-[4,6-bis(3,7-dioxaazabicyclo[3.3.1]nonanyl)-1,3,5-triazinyl] (difluoromethyl)pyridinamine; 4-(difluoromethyl)[4-(3,7-dioxaazabicyclo[3.3.1]nonanyl)(3-oxa 25 azabicyclo[3.2.1]octanyl)-1,3,5-triazinyl]pyridinamine; 5-[4,6-bis(3,3-dimethylmorpholinyl)-1,3,5-triazinyl](difluoromethyl)pyridinamine; 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridin- 2-amine; 5-[4,6-bis[(3R)methylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridin 30 amine; 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)morpholino-1,3,5-triazinyl]pyridin- 2-amine; 4-(difluoromethyl)[4-[(3R,5S)-3,5-dimethylmorpholinyl][(3R)methylmorpholin yl]-1,3,5-triazinyl]pyridinamine; 35 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[(3R)methylmorpholinyl]-1,3,5- triazinyl]pyridinamine; 17511707_1 (GHMatters) P42872NZ00 4-(difluoromethyl)[4-[(3R)(methoxymethyl)morpholinyl][(3R) methylmorpholinyl]-1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-(3,7-dioxaazabicyclo[3.3.1]nonanyl)[(3R) methylmorpholinyl]-1,3,5-triazinyl]pyridinamine; 5 (4S,5R)[4-[2-amino(difluoromethyl)pyrimidinyl]morpholino-1,3,5-triazinyl] (hydroxymethyl)methyl-oxazolidinone; )[6-[2-amino(difluoromethyl)pyrimidinyl]morpholino-pyrimidinyl] (hydroxymethyl)methyl-oxazolidinone; 4-(difluoromethyl)[4-[(3R)methylmorpholinyl](3-oxaazabicyclo[3.1.1]heptan- 10 6-yl)-1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-[(3R)methylmorpholinyl](6-oxaazabicyclo[3.1.1]heptan- 3-yl)-1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-[(3R)methylmorpholinyl][(1R,4R)oxa azabicyclo[2.2.1]heptanyl]-1,3,5-triazinyl]pyridinamine; 15 luoromethyl)[4-[(3R)methylmorpholinyl][(1S,4S)oxa azabicyclo[2.2.1]heptanyl]-1,3,5-triazinyl]pyridinamine; -bis[(3R)ethylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridinamine; 5-[4,6-bis(8-oxaazaspiro[3.5]nonanyl)-1,3,5-triazinyl](difluoromethyl)pyridin amine; 20 5-[4,6-bis[(3R)isopropylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridin amine; 5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl][(3R)methylmorpholin- 4-yl]-1,3,5-triazinyl](difluoromethyl)pyridinamine; 5-[4-[(4aS,7aR)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl][(3R) 25 methylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridinamine; 4-(difluoromethyl)[4-(4,4-difluoropiperidyl)[(3R)methylmorpholinyl]-1,3,5- triazinyl]pyridinamine; 4-(difluoromethyl)[4-[(3R)methylmorpholinyl](2-oxaazaspiro[3.5]nonanyl)- 1,3,5-triazinyl]pyridinamine; 30 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[(3R,5S)-3,5-dimethylmorpholin yl]-1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[(3R)(methoxymethyl)morpholin- 4-yl]-1,3,5-triazinyl]pyridinamine; [(3R)[4-[6-amino(difluoromethyl)pyridyl](3,3-dimethylmorpholinyl)-1,3,5- 35 triazinyl]morpholinyl]methanol; 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)(3,7-dioxa 17511707_1 (GHMatters) P42872NZ00 azabicyclo[3.3.1]nonanyl)-1,3,5-triazinyl]pyridinamine; 5-[4-(4-cyclopropylpiperazinyl)(3,3-dimethylmorpholinyl)-1,3,5-triazinyl] (difluoromethyl)pyridinamine; 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[4-(2-methoxyethyl)piperazinyl]- 5 1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)(1,1-dioxo-1,4-thiazinanyl)-1,3,5- triazinyl]pyridinamine; [(3R)[4-[6-amino(difluoromethyl)pyridyl][(3R)methylmorpholinyl]-1,3,5- triazinyl]morpholinyl]methanol; 10 4-(difluoromethyl)[4-[(3R,5R)-3,5-dimethylmorpholinyl][(3R)methylmorpholin yl]-1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-[(3S,5S)-3,5-dimethylmorpholinyl][(3R)methylmorpholin yl]-1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-morpholino(3-oxaazabicyclo[3.3.1]nonanyl)-1,3,5-triazin 15 yl]pyridinamine; 5-[4,6-bis(3-oxaazabicyclo[3.3.1]nonanyl)-1,3,5-triazinyl](difluoromethyl)pyridin- 2-amine; 5-[4-[6-amino(difluoromethyl)pyridyl](3,7-dioxaazabicyclo[3.3.1]nonanyl)- 1,3,5-triazinyl](difluoromethyl)pyridinamine; 20 4-(difluoromethyl)[4-[(3R)methylmorpholinyl](4-morpholinopiperidyl)-1,3,5- triazinyl]pyridinamine; 5-[4-(4-cyclopropylpiperazinyl)[(3R)methylmorpholinyl]-1,3,5-triazinyl] (difluoromethyl)pyridinamine; 5-[4-(4-cyclopropylpiperazinyl)[(3S,5R)-3,5-dimethylmorpholinyl]-1,3,5-triazin 25 yl](difluoromethyl)pyridinamine; 4-(difluoromethyl)[4-[4-(2-methoxyethyl)piperazinyl][(3R)methylmorpholinyl]- 1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-[(3S,5R)-3,5-dimethylmorpholinyl][4-(2- yethyl)piperazinyl]-1,3,5-triazinyl]pyridinamine; 30 luoromethyl)[4-(1,1-dioxo-1,4-thiazinanyl)[(3R)methylmorpholinyl]- 1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-[(3S,5R)-3,5-dimethylmorpholinyl](1,1-dioxo-1,4-thiazinan 3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-[(3R,5S)-3,5-dimethylmorpholinyl](3,7-dioxa 35 azabicyclo[3.3.1]nonanyl)-1,3,5-triazinyl]pyridinamine; 3-[4-[6-amino(difluoromethyl)pyridyl][(3R,5S)-3,5-dimethylmorpholinyl]-1,3,5- 17511707_1 (GHMatters) P42872NZ00 triazinyl]oxazolidinone; 5-(4-((1R,2R,4S,5S)oxaazatricyclo[3.3.1.02,4]nonanyl)((2R,4S)oxa cyclo[3.3.1.02,4]nonanyl)-1,3,5-triazinyl)(difluoromethyl)pyridinamine; 5-[4,6-bis(6,6-difluorooxaazabicyclo[3.2.1]octanyl)-1,3,5-triazinyl] 5 (difluoromethyl)pyridinamine; 5-[4,6-bis(6,7-difluorooxaazabicyclo[3.2.1]octanyl)-1,3,5-triazinyl] (difluoromethyl)pyridinamine; 6-aminopyridyl)[(3R)methylmorpholinyl]-1,3,5-triazinyl] (difluoromethyl)pyridinamine.
6. The compound of formula (I) ing to claim 5, wherein said compound is selected from the group consisting of - 4-(difluoromethyl)(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine; - 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxaazabicyclo[3.2.1]octanyl)-1,3,5- 15 triazinyl)(difluoromethyl)pyridinamine; - 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)morpholino-1,3,5-triazinyl) (difluoromethyl)pyridinamine; - 5-(4,6-bis((S)methylmorpholino)-1,3,5-triazinyl)(difluoromethyl)pyrimidin amine; 20 - (S)(difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazinyl)pyridin- 2-amine; - 4-(difluoromethyl)(4-morpholino(piperazinyl)-1,3,5-triazinyl)pyrimidinamine; - 4-(difluoromethyl)(4,6-dimorpholino-1,3,5-triazinyl)pyridinamine; and - (difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazin 25 yl)pyrimidinamine; and ers, solvates and pharmaceutically acceptable salts thereof.
7. The compound of formula (I) according to claim 6, wherein said compound is selected from, 30 - 4-(difluoromethyl)(4,6-dimorpholino-1,3,5-triazinyl)pyrimidinamine; - 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)(3-oxaazabicyclo[3.2.1]octanyl)-1,3,5- triazinyl)(difluoromethyl)pyridinamine; - (S)(difluoromethyl)(4-(3-methylmorpholino)morpholino-1,3,5-triazinyl)pyridin- 2-amine; 35 and tautomers, solvates and pharmaceutically acceptable salts thereof. 17511707_1 (GHMatters) P42872NZ00
8. The nd of formula (I) according to claim 5, wherein said compound is selected from 4-[4-[6-amino(difluoromethyl)pyridyl]morpholino-1,3,5-triazinyl]morpholin one; 5 4-[4-[2-amino(difluoromethyl)pyrimidinyl]morpholino-1,3,5-triazinyl]morpholin one; 5-[4,6-bis(3,7-dioxaazabicyclo[3.3.1]nonanyl)-1,3,5-triazinyl] (difluoromethyl)pyridinamine; 4-(difluoromethyl)[4-(3,7-dioxaazabicyclo[3.3.1]nonanyl)(3-oxa 10 azabicyclo[3.2.1]octanyl)-1,3,5-triazinyl]pyridinamine; 5-[4,6-bis(3,3-dimethylmorpholinyl)-1,3,5-triazinyl](difluoromethyl)pyridinamine; 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridin- 2-amine; -bis[(3R)methylmorpholinyl]-1,3,5-triazinyl](difluoromethyl)pyridin 15 amine; 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)morpholino-1,3,5-triazinyl]pyridin- 2-amine; 4-(difluoromethyl)[4-[(3R,5S)-3,5-dimethylmorpholinyl][(3R)methylmorpholin yl]-1,3,5-triazinyl]pyridinamine; 20 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[(3R)methylmorpholinyl]-1,3,5- triazinyl]pyridinamine; luoromethyl)[4-[(3R)(methoxymethyl)morpholinyl][(3R) methylmorpholinyl]-1,3,5-triazinyl]pyridinamine; 4-(difluoromethyl)[4-(3,7-dioxaazabicyclo[3.3.1]nonanyl)[(3R) 25 methylmorpholinyl]-1,3,5-triazinyl]pyridinamine; (4S,5R)[4-[2-amino(difluoromethyl)pyrimidinyl]morpholino-1,3,5-triazinyl] (hydroxymethyl)methyl-oxazolidinone.
9. The compound of formula (I) according to any one of the claims 1 to 4, wherein R1 30 and R2 are independently of each other a morpholinyl of formula (II).
10. The compound of formula (I) according to claim 9, wherein R1 is equal to R2.
11. The compound of formula (I) according to claim 9, wherein R1 is not equal to R2. 17511707_1 (GHMatters) P42872NZ00
12. The compound of formula (I) according to any one of the claims 1 to 4, wherein R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 5- to 6-membered heterocyclic ring Z. 5
13. The nd of formula (I) according to claim 12, wherein said 5- to 6- membered heterocyclic ring Z is selected from
14. A pharmaceutical composition comprising a compound of a (I) according to 15 any one of the claims 1 to 13 and a pharmaceutically acceptable carrier.
15. Use of a compound of formula (I) according to any one of the claims 1 to 13 in the preparation of a medicament for the treatment or prevention of a disease or condition ted by PI3Ks and/or mTOR and/or PIKKs in a human.
16. The use of a compound according to claim 15, wherein said disease or disorder is a hyperproliferative disorder. 07_1 (GHMatters) P42872NZ00
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14192617 | 2014-11-11 | ||
EP14192617.0 | 2014-11-11 | ||
PCT/EP2015/076192 WO2016075130A1 (en) | 2014-11-11 | 2015-11-10 | Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines |
Publications (2)
Publication Number | Publication Date |
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NZ731504A NZ731504A (en) | 2021-04-30 |
NZ731504B2 true NZ731504B2 (en) | 2021-08-03 |
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