HK1162482B

HK1162482B - Pyrazine derivatives useful as inhibitors of atr kinase

Info

Publication number: HK1162482B
Application number: HK12102832.4A
Authority: HK
Inventors: J-D‧凯瑞尔; S‧迪朗特; D‧凯; R‧克内格特尔; S‧麦克考米克; M‧莫蒂默尔; M‧奥当耐尔; J‧平德; A‧拉瑟福德; A‧N‧维拉尼; S‧杨; P‧M‧瑞普尔
Original assignee: 沃泰克斯药物股份有限公司
Priority date: 2008-12-19
Filing date: 2009-12-18
Publication date: 2018-02-02

Description

Compounds useful as inhibitors of ATR kinase

Background

ATR ("ATM and Rad 3 related") kinases are protein kinases that are implicated in cellular responses to DNA damage. ATR kinase works with ATM ("dyskinetic telangiectasia mutated") kinase and many other proteins to modulate cellular responses to DNA damage, commonly referred to as DNA damage responses ("DDR"). DDR stimulates DNA repair, promotes survival and halts cell cycle progression by activating cell cycle checkpoints, thereby providing repair time. Without DDR, cells are much more sensitive to DNA damage and are prone to death from endogenous cellular processes such as DNA replication or DNA damage induced by exogenous DNA damaging agents commonly used in cancer therapy.

Healthy cells may depend on the host of different proteins for DNA repair including DDR kinase ATR. In some cases, these proteins can compensate for each other by activating functional redundant DNA repair processes. In contrast, many cancer cells harbor defects in some of their DNA repair processes, such as ATM signaling, and thus exhibit great dependence on their remaining intact DNA repair proteins, including ATR.

In addition, many cancer cells express activated oncogenes or lack critical tumor suppressor genes, and this can predispose these cancer cells to a dysregulated stage of DNA replication, thereby causing DNA damage. ATR involves a key component of DDR as a response to impaired DNA replication. As a result, these cancer cells are more dependent on ATR activity for survival than healthy cells. ATR inhibitors may therefore be useful in cancer therapy, either alone or in combination with DNA damaging agents, because they switch off the DNA replication machinery that is more important for cell survival in cellular cancer cells than in healthy normal cells. Indeed, ATR inhibition has been demonstrated to be effective as a single active agent in cancer cells and as a potent sensitizer for radiotherapy and genotoxic chemotherapy.

The ATR peptide can be expressed and isolated using various methods known in the literature (see, e.g., for exampleEt al, PNAS 99: 10, pp6673-6678, 5 months and 14 days in 2002; see also Kumagai et al, Cell 124, pp943-955, 3.10.2006; Unsal-Kacmaz et al, Molecular and Cellular Biology, 2.2004, p 1292-1300; and Hall-Jackson et al, Oncogene 1999, 18, 6707-.

For all of these reasons, there is a need to develop effective and selective ATR inhibitors for the treatment of cancer, either as single agents or as combination therapies in combination with radiation therapy or genotoxic chemotherapy.

Summary of The Invention

The present invention relates to pyrazine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of the invention; methods of using the compounds of the invention in the treatment of various diseases, disorders, and conditions; a process for the preparation of the compounds of the invention; intermediates for the preparation of the compounds of the invention; and methods of using the compounds in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and comparative evaluation of novel kinase inhibitors. These compounds have surprising ability to treat cancer as single agents. These compounds also show surprising synergy in combination therapy with other cancer drugs such as cisplatin.

Detailed Description

One aspect of the present invention provides a compound of formula IA:

or a pharmaceutically acceptable salt thereof; wherein

Y is C ₁-C₁₀An aliphatic chain, wherein up to three methylene units of said aliphatic chain are optionally O, NR⁰S, C (O) or S (O)₂Replacement;

ring A is a 5-membered heteroaryl ring selected from

J³Is H or C_1-4Alkyl, wherein 1 methylene unit of the alkyl may optionally be replaced by O, NH, N (C)_1-4Alkyl) or S and optionally substituted with 1-3 halogens;

q is a 5-6 membered monocyclic aromatic ring comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic aromatic ring comprising 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R⁵is H; a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-10 membered bicyclic fully saturated, partially unsaturated, or aromatic ring comprising 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r⁵Optionally substituted by 1-5J⁵Substituted by groups;

l is C_1-4An alkyl chain wherein up to 2 methylene units of the alkyl chain are optionally O, NR⁶S, -C (O) -, -SO-or-SO₂-substitution;

R⁰is H or C₁-C₆Alkyl, wherein 1 methylene unit of the alkyl chain mayOptionally with O, NH, N (C)_1-4Alkyl) or S substitution;

R¹is H or C₁-C₆An alkyl group;

R²is H, C₁-C₆Alkyl, - (C) ₂-C₆Alkyl) -Z or a 4-8 membered ring containing 0-2 nitrogen atoms; j wherein the rings are bonded through a carbon atom and are optionally substituted by 1 occurrence^ZSubstitution;

or R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur; j wherein said heterocycle is optionally substituted by 1 occurrence^Z1Substitution;

J^Z1is halogen, CN, C₁-C₈Aliphatic radical, - (X)_t-CN or- (X)_r-Z; wherein said C₁-C₈Up to 2 methylene units of an aliphatic radical may optionally be replaced by O, NR, S, P (O), C (O), S (O), or S (O)₂Replacement; wherein said C₁-C₈The aliphatic radical being optionally substituted by halogen, CN or NO₂Substitution;

x is C₁-C₄An alkyl group;

t, r and m are each independently 0 or 1;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

or R³And R⁴Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur; j wherein said ring is optionally substituted with 1 occurrence^ZSubstitution;

R⁶is H or C₁-C₆An alkyl group;

J^Zindependently is NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO(C_1-4Aliphatic group), CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group;

J⁵is halogen, oxo, CN, NO ₂、X¹-R or- (X)¹)_p-Q⁴；

X¹Is C_1-10An aliphatic group; wherein said C_1-101-3 methylene units of an aliphatic radical are optionally substituted by-NR '-, -O-, -S-, C (═ NR'), C (O), S (O)₂Or S (O) substitution; wherein X¹NH optionally and independently present 1 to 4 times₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic group), C (O) NH₂、C(O)NH(C_1-4Aliphatic radical), C (O) N (C)_1-4Aliphatic radical)₂、SO(C_1-4Aliphatic group), SO₂(C_1-4Aliphatic group), SO₂NH(C_1-4Aliphatic group), SO₂NH(C_1-4Aliphatic group), NHC (O) (C)_1-4Aliphatic radical), N (C)_1-4Aliphatic radical) C (O) (C_1-4Aliphatic radical), wherein said C is_1-4Aliphatic groups are optionally substituted with 1-3 occurrences of halogen;

Q⁴is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur or an 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; q⁴Each optionally substituted by 1-5J^Q4Substitution;

J^Q4is halogen, CN or C_1-4Alkyl, wherein up to 2 methylene units are optionally substituted by O, NR, S, C (O), S (O) or S (O)₂Replacement;

r is H or C_1-4Alkyl radical, wherein said C_1-4Alkyl is optionally substituted with 1-4 halogens;

J²is halogen; CN; a 5-6 membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or C _1-10Aliphatic radical in which up to 2 methylene units are optionally substituted by O, NR', C (O), S, S (O) or S (O)₂Replacement; wherein said C_1-10Aliphatic groups are optionally substituted with 1-3 halogens or CN; and said monocyclic ring is optionally substituted with 1-3 occurrences of halo, CN; c_3-6A cycloalkyl group; a 3-7 membered heterocyclic group containing 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; or C_1-4Alkyl, wherein up to 1 methylene unit of the alkyl chain is optionally replaced by O, NR' or S; and wherein said C_1-4Alkyl is optionally substituted with 1-3 halogens;

q is 0, 1 or 2;

p is 0 or 1;

r ', R' and R are each independently H, C_1-4Alkyl or absent; wherein said C_1-4Alkyl is optionally substituted with 1-4 halogens.

In some embodiments of the present invention, the substrate is,

y is C₁-C₆An aliphatic chain in which 1 methylene unit of the alkyl chain is optionally substituted by C (O) or-NR⁰-substitution; and is

R⁵Is a 3-7 membered monocyclic fully saturated, partially unsaturated or aromatic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or an 8-10 membered bicyclic fully saturated, partially unsaturated, or aromatic ring containing 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r⁵Optionally substituted by 1-5J⁵Substituted with radicals provided that when ring A is When, p is 1; and R is⁵Is aromatic.

In some embodiments, ring a is a 5-membered heteroaryl ring selected from

In some embodiments, ring a is

In other embodiments, ring a is

It is understood that the ring a structure can be bonded to the pyrazine ring in two different ways: pulled out and inverted (flipped). For example, when ring A isWhen the current is over; it is understood that the pyrazine ring is shown below:

pulled-out and reversed "

Similarly, when ring A isIt may also be bonded to the pyrazine ring in two ways- -as pulled and inverted. In some embodiments, the ring a structure is bonded in a pull-out manner.

In other embodiments, J³Is H.

In other embodiments, Y is C_1-2An alkyl chain wherein 1 methylene unit of the alkyl chain is optionally substituted with-NR⁰-substitution.

In some embodiments, J is⁵Is C_1-6An aliphatic group in which up to 2 methylene units are optionally replaced by O or NR 'R' wherein R 'and R' are each independently H or alkyl; or R 'and R' together form a 3-6 membered heterocyclic ring; NH (NH)₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO(C_1-4Aliphatic group), CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C _1-4An aliphatic group;

in other embodiments, J²Is halogen, C optionally substituted by 1-3 fluorine₁-C₂Alkyl, CN or C_1-4Alkyl, in which up to 2 methylene units are optionally substituted by S (O), S (O)₂C (O) or NR'.

In a further embodiment of the process of the present invention,

y is NH;

R⁵is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, R⁵Optionally fused to a 5-6 membered aromatic ring containing 0-2 heteroatoms selected from N, O or S; r⁵Each optionally substituted by 1-5J⁵Substituted by groups;

l is-C (O) -or-SO₂-；

R¹Is H or C₁-C₆An alkyl group;

R²is- (C) containing 0 to 2 nitrogen atoms₂-C₆Alkyl) -Z or a 4-8 membered ring; j wherein the rings are bonded through a carbon atom and are optionally substituted by 1 occurrence^ZSubstitution;

or R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms; j wherein said heterocycle is optionally substituted by 1 occurrence^Z1Substitution;

J^Z1is- (X)_t-CN、C₁-C₆Alkyl or- (X)_r-Z；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

J⁵is halogen, NO₂CN, O (halogenated C)_1-4Aliphatic group), halogenated C _1-4Aliphatic radicals or C_1-6Aliphatic groups in which up to 2 methylene units are optionally replaced by c (O), O or NR'; and is

J²Is halogen, C optionally substituted by 1-3 fluorine₁-C₂Alkyl or CN.

According to another embodiment, L is-C (O) -, m is 0, R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms. In some embodiments, the heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1, 4-diazepanyl.

According to another embodiment, m is 0, q is 0, -L-NR¹R²Is C (O) pyrrolidinyl, C (O) piperidinyl, C (O) piperazinyl, C (O) azepanyl, C (O)1, 4-diazepanyl, C (O) NH-piperidinyl, C (O) NHCH₂CH₂Pyrrolidinyl, C (O) NHCH₂CH₂-piperidinyl, CON (CH)₃)CH₂CH₂N(CH₃)₂Wherein said pyrrolidinyl, piperidinyl, piperizinyl(iv) oxazinyl, azepanyl or 1, 4-diazepanyl optionally substituted by C_1-4Alkyl or N (C)_1-4Alkyl radical)₂And (4) substitution.

According to another embodiment, J²Is halogen; CN; a phenyl group; an oxazolyl group; or C_1-6Aliphatic radical in which up to 2 methylene units are optionally substituted by O, NR', C (O), S, S (O) or S (O)₂Replacement; said C is_1-6The aliphatic group is optionally substituted with 1-3 fluorines or CN.

Another embodiment provides a compound of formula I A':

or a pharmaceutically acceptable salt thereof; wherein

Y is C₁-C₄An alkyl chain wherein 1 methylene unit of the alkyl chain is optionally substituted with-NR⁰-substitution;

g is O or S;

R⁵is a 3-7 membered monocyclic fully saturated, partially unsaturated or aromatic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or an 8-10 membered bicyclic fully saturated, partially unsaturated, or aromatic ring containing 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r⁵Optionally substituted by 1-5J⁵Substituted by groups;

R⁰is H or C₁-C₆An alkyl group;

R¹is H or C₁-C₆An alkyl group;

R²is H, C₁-C₆Alkyl, - (C)₂-C₆Alkyl) -Z or a 4-8 membered ring containing 0-2 nitrogen atoms; j wherein the rings are bonded through a carbon atom and are optionally substituted by 1 occurrence^ZSubstitution;

or R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, sulfur or oxygen; j wherein said heterocycle is optionally substituted by 1 occurrence ^Z1Substitution;

J^Z1is- (X)_t-CN、C₁-C₆Alkyl or- (X)_r-Z；

X is C₁-C₄An alkyl group;

t, r and m are each independently 0 or 1;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

or R³And R⁴Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms; j wherein said ring is optionally substituted with 1 occurrence^ZSubstitution;

R⁶is H or C₁-C₆An alkyl group;

J⁵is halogen, oxo, CN, NO₂、X¹-R or- (X)¹)_p-Q⁴，

X¹Is C_1-10An aliphatic group; wherein said C_1-101-3 methylene units of an aliphatic radical are optionally substituted by-NR' -, -O-, -S-, C (O), S (O)₂Or S (O) substitution; wherein X¹NH optionally and independently present 1 to 4 times₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic group), C (O) NH₂、C(O)NH(C_1-4Aliphatic radical), C (O) N (C)_1-4Aliphatic radical)₂、SO(C_1-4Aliphatic group), SO₂(C_1-4Aliphatic group), SO₂NH(C_1-4Aliphatic group), SO₂NH(C_1-4Aliphatic group), NHC (O) (C)_1-4Aliphatic radical), N (C)_1-4Aliphatic radical) C (O) (C_1-4Aliphatic radical), wherein said C is_1-4Aliphatic groups are optionally substituted with 1-3 occurrences of halogen;

J²is halogen; CN; has a value of 0 to 3A 5-6 membered aromatic or non-aromatic monocyclic ring of heteroatoms selected from oxygen, nitrogen or sulfur; or C_1-10Aliphatic radical in which up to 2 methylene units are optionally substituted by O, NR', C (O), S, S (O) or S (O)₂Replacement; wherein said C_1-10Aliphatic groups are optionally substituted with 1-3 halogens or CN; and said monocyclic ring is optionally substituted with 1-3 halogens; CN; c_3-6A cycloalkyl group; a 3-7 membered heterocyclic group containing 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; or C_1-4Alkyl, wherein up to 1 methylene unit of the alkyl chain is optionally replaced by O, NR' or S;

q is 0, 1 or 2;

p is 0 or 1.

In some embodiments, J is⁵Is halogen, NO₂CN, O (halogenated C)_1-4Aliphatic group), halogenated C_1-4Aliphatic radicals or C_1-6An aliphatic group in which up to 2 methylene units are optionally replaced by C (O), O or NR'. In other embodiments, J⁵Is halogen, CN, phenyl, oxazolyl or C_1-6Aliphatic radical in which up to 2 methylene units are optionally O, NR', C (O), S, S (O) or S (O)₂Replacement; said C is_1-6The aliphatic group is optionally substituted with 1-3 fluorines or CN.

In other embodiments, J²Is halogen; CN; a phenyl group; an oxazolyl group; or C_1-6Aliphatic radical in which up to 2 methylene units are optionally substituted by O, NR', C (O), S, S (O) or S (O)₂Replacement; said C is_1-6The aliphatic group is optionally substituted with 1-3 fluorines or CN.

In some embodiments, Y is C₁-C₂An alkyl chain wherein 1 methylene unit of the alkyl chain is optionally substituted with NR⁰And (4) replacing.

In some embodiments, p is 0 and Q is phenyl, indolyl, pyridyl, naphthyl or benzothienyl or quinolinyl. In some embodiments, Q is phenyl, indolyl, pyridinyl, or quinolinyl. In some embodiments, Q is phenyl or pyridyl. In some embodiments, Q is phenyl. In other embodiments, Q is pyridyl.

J²is-OCH₃、-OCH₂CH₂N(CH₃)₂、-NHCH₂CH₂N(CH₃)₂Or a piperazinyl group.

The compound of claim 19, wherein Q is substituted at the ortho, para, or both ortho and para positions.

The compound of claim 19 wherein Q is substituted at the para position by J²Is substituted, wherein J²Is C_1-6Aliphatic radical in which the methylene group bonded to the ring Q is replaced by-SO₂-substitution.

The compound of claim 19 wherein at least 1 or more methylene units C_1-6The aliphatic group is optionally replaced by a heteroatom selected from O, NR "and S.

The compound of claim 19, wherein Q is para-SO₂(C_1-4Alkyl), -SO₂(C_1-4Alkyl) N (C)_1-4Alkyl radical)₂、C(O)N(C_1-4Alkyl radical)₂C (O) (1, 4-diazepanyl), CO (azepanyl), C (O) (piperazinyl) or C (O) (piperidinyl).

The compound of claim 21, wherein C_1-6At least 1 or more methylene units of the aliphatic group are optionally replaced by a heteroatom selected from O, NR "and S.

In some embodiments, Q is optionally substituted at the ortho position with 1, wherein J²Is C₁-C₄Alkyl, NH₂、NHC(O)CH₃、O(C₁-C₄Alkyl), CH₂OH、CH₂OCH₃、CH₂CH₂OCH₃、CH₂CN、CN、CH₂C(O)NH₂、OH、OCF₃、CF₃、CHF₂、-CH＝CHF、NHCOCH₃、COCH₃、CONH₂、SCH₃、SOCH₃、SOCH₂CH₃、SO₂CH(CH₃)₂-C ≡ CH, oxazolyl or phenyl. In some embodiments, J is²In ortho position by CH₂OH、CHF₂、S(O)CH₃Or S (O) CH₂CH₃And (4) substitution.

In other embodiments, Q is optionally substituted with J at the ortho position²Is substituted, wherein J²Is C_1-4Alkyl, -C ≡ C- (C) _1-4Alkyl), CH ═ CH₂、CH＝CHF、O(C_1-4Alkyl), NH (C)_1-4Alkyl group), N (C)_1-4Alkyl radical)₂、-(C_1-4Alkyl) OH, - (C)_1-4Alkyl) O (C)_1-4Alkyl), - (C)_1-4Alkyl) NH₂、-(C_1-4Alkyl) NH (C)_1-4Alkyl), - (C)_1-4Alkyl) N (C)_1-4Alkyl radical)₂、-(C_1-4Alkyl) CN, CO (C)_1-4Alkyl), CON (C)_1-4Alkyl radical)₂、C(O)O(C_1-4Alkyl), S (C)_1-4Alkyl), -S- (C)_1-4Alkyl) NH₂、S(O)(C_1-4Alkyl) NH₂、S(O)₂(C_1-4Alkyl) OH, S (O) (C)_1-4Alkyl) NHC (O) O (tert-butyl), NHS (O)₂(C_1-4Alkyl), halogen or CN.

In some embodiments, J is²Is CH₂CH₂OH、SCH(CH₃)₂、-C≡CCH₃Halogen, CN, CON (CH)₃)₂、CH₂CN、S(O)CH₂CH₂NH₂、SCH₂CH₂NH₂、C(O)OCH₃、CH₂N(CH₃)₂、S(O)CH₂CH₂NHBOC、N(CH₃)₂、NHSO₂CH₃、CH＝CHF、CH₂OCH₃、CH＝CH₂、SCH₂CH₃or-CH ═ CH.

In other embodiments, Q is optionally J in the para position²Is substituted, wherein J²is-SO₂(C_1-4Alkyl), -SO₂(C_3-6Cycloalkyl), -SO₂(3-6-membered heterocyclic group), -SO₂(C_1-4Alkyl) N (C)_1-4Alkyl radical)₂、-C(O)(C_1-4Alkyl), - (C)_1-4Alkyl) N (C)_1-4Alkyl radical)₂or-NHC (O) (C)_1-4Alkyl groups).

In some embodiments, the 3-6 membered heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

In other embodiments, Q is optionally substituted with J in the meta position²Is substituted, wherein J²Is C_1-4Alkyl radical, C_1-4Alkoxy, halogen, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, CN, SO₂(C_1-4Alkyl), NHSO₂(C_1-4Alkyl group), C (O) (C)_1-4Alkyl), C (O) NH₂、NHC(O)(C_1-4Alkyl), - (C)_1-4Alkyl) -OH, - (C)_1-4Alkyl) -O (C)_1-4Alkyl), - (C)_1-4Alkyl) -NH₂、-(C_1-4Alkyl) -N (C)_1-4Alkyl radical)₂Or- (C) _1-4Alkyl) NH (C)_1-4Alkyl groups).

In some embodiments, Q is naphthyl or benzothienyl.

In another embodiment, Q is pyridinyl. In some embodiments, Q is substituted with one J in the ortho position²Is substituted, wherein J²Is CN.

In some embodiments, Q is optionally substituted with one or two J²Is substituted, wherein J²Is C_1-6An aliphatic radical in which up to 2 methylene units are optionally replaced by O or NR'.

In some casesIn the embodiment, J²is-OCH₃、-OCH₂CH₂N(CH₃)₂、-NHCH₂CH₂N(CH₃)₂Or a piperazinyl group.

In another embodiment, p is 1. In some embodiments, Q is phenyl, pyridyl, or naphthyl. In some embodiments, the pyridyl is 3-pyridyl or 4-pyridyl. In other embodiments, Q is phenyl.

In some embodiments, Q comprises Q¹And optionally Q¹As shown in formula IA-i, wherein Q¹Is a 6-membered ring and-LNR¹R²Substitutions in para position are shown below:

in some embodiments, J is⁵Is halogen, NO₂CN, O (halogenated C)_1-4Aliphatic group), halogenated C_1-4Aliphatic radicals or C_1-6An aliphatic group in which up to 2 methylene units are optionally replaced by C (O), O or NR'.

In some embodiments, Q¹Is phenyl or pyridyl. In other embodiments, Q¹-Q²Is naphthyl.

In other embodiments, L is-C (O) -or-SO₂-。

In other embodiments, R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, sulfur or oxygen. In some embodiments, the heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1, 4-diazepanyl, or 14-oxazepanyl. In other embodiments, R¹Is C₁-C₆An alkyl group. In some embodiments, the heterocycle is optionally substituted with halogen, CN, C_1-6Aliphatic radical, halogeno C_1-6Aliphatic radical, -C (O) O (C)_1-6Aliphatic radical), C (O) H, C (O) (C)_1-6Aliphatic radical), P (O) (OC)_1-4Alkyl radical)₂、NH(C_1-6Aliphatic radical) or N (C)_1-6Aliphatic radical)₂And (4) substitution.

In some embodiments, R²Is C₁-C₆An alkyl group. In other embodiments, R²Is- (C)₂-C₆Alkyl) -Z.

According to another embodiment, m is 0.

According to another embodiment, q is 0.

In some embodiments, L is-C (O) -.

In some embodiments, R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms. In some embodiments, the heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1, 4-diazepanyl. In other embodiments, the heterocycle is selected from

In some embodiments, t is 1. In other embodiments, t is 0.

In other embodiments, R¹Is H or C₁-C₆An alkyl group; r²Is- (C)₂-C₆Alkyl) -Z. In some embodiments, R¹Is C₁-C₆An alkyl group. In some embodiments, Z is-NR³R⁴Wherein R is³And R⁴Are all C₁-C₂An alkyl group. In other embodiments, R³And R⁴Together with the atoms to which they are attached form a ring selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl. In some embodiments, the ring is pyrrolidinyl or piperidinyl.

In some embodiments, the ring is optionally substituted with 1J^Z1And (4) substitution. In some embodiments, J is^Z1Is (X)_r-Z. In other embodiments, J^Z1Is C_1-4Alkyl or N (C)_1-4Alkyl radical)₂。

In one embodiment, p is 0, q is 0, -L-NR¹R²Is C (O) pyrrolidinyl, C (O) piperidinyl, C (O) piperazinyl, C (O) azepanyl, C (O)1, 4-diazepanyl, C (O) NH-piperidinyl, C (O) NHCH₂CH₂Pyrrolidinyl, C (O) NHCH₂CH₂-piperidinyl, CON (CH)₃)CH₂CH₂N(CH₃)₂Wherein said pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl is optionally substituted with C_1-4Alkyl or N (C)_1-4Alkyl radical) ₂And (4) substitution. In one embodiment, -L-NR¹R²Is C (O)1, 4-diazepanyl.

According to another aspect, m is 0. In some embodiments, R⁵Is thienyl, thiazolyl, furyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, pyridonyl, pyridinyl, tetrahydropyridinyl, tetrahydroisoquinolinyl, 1, 4-diazepanyl, azabicyclo [2.2.1]Heptaalkyl or phenyl. In other embodiments, R⁵Is phenyl, piperidinyl or thienyl. In some embodiments, Q is optionally substituted with-SO in para position₂(C_1-4Alkyl), -SO₂(C_1-4Alkyl) N (C)_1-4Alkyl radical)₂、C(O)N(C_1-4Alkyl radical)₂C (O) (1, 4-diazepanyl), C (O) (piperazinyl) or C (O) (piperidinyl).

According to anotherAspect, R⁵Is phenyl. In some embodiments, R⁵Optionally substituted by 1-2J⁵Is substituted by radicals in which J⁵Selected from halogen, CN, NO₂、X¹-R or- (X)¹)_p-Q⁴(ii) a p is 0 to 1; x¹Is C_1-10Aliphatic radical, wherein said C_1-61-3 methylene units of an aliphatic radical are optionally substituted by-NR' -, -O-, -S-, C (═ NH) -, C (O), S (O)₂Or S (O) substitution; r is H; q⁴Is a 3-6 membered monocyclic ring containing 0-2 heteroatoms selected from O or N, wherein X¹Optionally substituted with 1-3 occurrences of halogen or CN.

In other embodiments, J⁵Is C_1-10An aliphatic chain, wherein X¹1-2 methylene units of (A) are replaced by-O-or-NR' -.

According to another aspect, R⁵Is optionally substituted by NH₂Or- (C)_1-4Alkyl) NH₂A substituted piperidinyl group. According to another aspect, R⁵Is optionally substituted by CN, C_1-6Alkyl, - (C)_1-4Alkyl) NH₂、-(C_1-4Alkyl) NH (C)_1-4Alkyl), - (C)_1-4Alkyl) N (C)_1-6Alkyl radical)₂、O(C_1-6Alkyl), pyrrolidinyl substituted thienyl, wherein said alkyl is optionally substituted with 1-3 halogens.

In some embodiments, Q⁴Is an optionally substituted 3-6 membered cycloalkyl ring. In other embodiments, Q⁴Is an optionally substituted 3-6 membered heterocyclic ring, said 3-6 membered heterocyclic ring being selected from pyrrolidinyl, azetidinyl or thienyl.

In some embodiments, J is⁵Is halogen, C_1-6Alkyl radical, NO₂、CN、C_1-6Alkyl, -CH ═ CH₂、OH、OCH₃、OCH₂CH₃、OCH(CH₃)₂、NH₂、CH₂NH₂、CH₂OH、CH(CH₃)NHCH₃、C(CH₃)₂NH₂、CH₂CH₂NH₂、CH₂CH₂OH、CH₂NHCH₃、CH₂N(CH₃)₂、CH(CH₃)NH₂、CH(CH₃)NHC(O)O(CH₃)₃、CH₂NHC(CH₃)₂、CH₂NHCH₂CHF₂、CH₂NHCH₂CH(CH₃)OH、CH₂NHCH₂C(CH₃)₂OH、CH₂NHCH₂CH (OH) -cyclopropyl, CH₂NHCH₂CH₂N(CH₃)₂、CH₂NHCH(CH₂CH₃)₃、CH₂NHCH₃、CH₂NHCH₂CH₃、CH₂NHCH₂CH₂CH₃、CH₂NH-cyclopropyl, CH₂NHCH₂CH₂OH、CH₂NHCH₂CH₂OCH₃、CH₂NHCH₂CH₂OCH₂CH₂OH, azetidinyl, pyrrolidinyl, CF₃、C(＝NH)NH₂、C(＝NH)NH(CH₃) Thienyl, CH₂NH-cyclopropyl, CH₂NH(CH₂OH)₃、OCH₂CH₂OH、OCH₂CH₂CH₂OH、OCH₂CH₂NHC(O)OC(CH₃)₃、CH₂NHC(O)O(CH₃)₃Or CH₂OC(O)CH₃。

According to another aspect, m is 1.

In some embodiments, R⁵Is H.

In some embodiments, Y is-NH-, -NHCH₂-、-NHC(O)-、C(O)NH、C(O)NHCH₂、C(O)、-NHCH(CH₃) -or-N (CH)₃)CH₂-；R⁵Is phenyl. In some embodiments, R⁵Optionally substituted by halogen or C_1-4Alkyl substituted wherein up to 1 methylene unit is optionally replaced by O, NR' or S.

Another embodiment provides a compound of formula IIA:

or a pharmaceutically acceptable salt thereof; wherein

Ring A is a 5-membered heteroaryl ring selected from

l is-C (O) -or-SO₂-；

R¹Is H or C₁-C₆An alkyl group;

R⁰is H or C₁-C₆An alkyl group;

R²is C₁-C₆Alkyl, - (C)₂-C₆Alkyl) -Z or a 4-8 membered ring containing 0-2 nitrogen atoms; j wherein the rings are bonded through a carbon atom and are optionally substituted by 1 occurrence^ZSubstitution;

or R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, sulfur or oxygen; j wherein said heterocycle is optionally substituted by 1 occurrence^Z1Substitution;

J^Z1is (X)_t-CN、C₁-C₆Alkyl or- (X)_r-Z；

X is C₁-C₄An alkyl group;

t, r and m are each independently 0 or 1;

Z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

J^Zis NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO(C_1-4Aliphatic group), CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group;

J⁵is halogen, NO₂CN, O (halogenated C)_1-4Aliphatic group), halogenated C_1-4Aliphatic radicals or C_1-6Aliphatic groups in which up to 2 methylene units are optionally replaced by c (O), O or NR';

J²is halogen; CN; a phenyl group; an oxazolyl group; or C_1-6Aliphatic radical in which up to 2 methylene units are optionally substituted by O, NR', C (O), S, S (O) or S (O)₂Replacement; said C is_1-6Aliphatic groups are optionally substituted with 1-3 fluorines or CN;

r 'and R' are each independently H or C₁-C₄An alkyl group;

q is 0, 1 or 2;

p is 0 or 1.

In some embodiments, Q is phenyl or pyridyl.

In other embodiments, Y is C₁-C₂An alkyl chain wherein 1 methylene unit of the alkyl chain is optionally substituted with NR⁰And (4) replacing.

Another embodiment provides a compound from table IIA-2:

TABLE IIA-2

Another embodiment provides a compound of formula IIIA:

or a pharmaceutically acceptable salt thereof; wherein

q is phenyl or pyridyl;

l is-C (O) -or-SO₂-；

R¹Is H or C₁-C₆An alkyl group;

R⁰is H or C₁-C₆An alkyl group;

J^Z1is- (X)_t-CN、C₁-C₆Alkyl or- (X)_r-Z；

X is C₁-C₄An alkyl group;

t, r and m are each independently 0 or 1;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

or R³And R⁴Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms; whereinJ wherein said ring is optionally substituted by 1 occurrence ^ZSubstitution;

r 'and R' are each independently H or C₁-C₄An alkyl group;

q is 0, 1 or 2;

p is 0 or 1.

In other embodiments, p is 0 and Q is pyridinyl. In some embodiments, m is 0.

In other embodiments, R⁵Is phenyl or thienyl. In some embodiments, R⁵Is NH optionally present 1 time₂、C₁-C₄Alkyl or CH₂NH₂A substituted phenyl group.

Another embodiment provides a compound selected from table IIIA:

TABLE IIIA

Another aspect provides a compound of formula IA-ii:

or a pharmaceutically acceptable salt thereof; wherein

Y is NH;

ring A is a 5-membered heteroaryl ring selected from

l is-C (O) -or-SO₂-；

R¹Is H or C₁-C₆An alkyl group;

R²is- (C)₂-C₆Alkyl) -Z or a 4-8 membered ring containing 0-2 nitrogen atoms; j wherein the rings are bonded through a carbon atom and are optionally substituted by 1 occurrence^ZSubstitution;

or R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms; j wherein said heterocycle is optionally substituted by 1 occurrence^Z1Substitution；

J^Z1Is- (X)_t-CN、C₁-C₆Alkyl or- (X)_r-Z；

X is C₁-C₄An alkyl group;

t, r and m are each independently 0 or 1;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

J^Z、J¹and J⁵Each independently is NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C) _1-4Aliphatic group), NO₂、CN、CO₂H、CO(C_1-4Aliphatic group), CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group;

J²is halogen, C optionally substituted by 1-3 fluorine₁-C₂Alkyl or CN;

q is 0, 1 or 2.

According to one embodiment, ring A is

According to another embodiment, m is 0.

According to another embodiment, q is 0.

In some embodiments, L is-C (O) -.

In some embodiments, t is 1. In other embodiments, t is 0.

In one embodiment, p is 0, q is 0, -L-NR¹R²Is C (O) pyrrolidinyl, C (O) piperidinyl, C (O) piperazinyl, C (O) azepanyl, C (O)1, 4-diazepanyl, C (O) NH-piperidinyl, C (O) NHCH₂CH₂Pyrrolidinyl, C (O) NHCH₂CH₂-piperidinyl, CON(CH₃)CH₂CH₂N(CH₃)₂Wherein said pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl is optionally substituted with C_1-4Alkyl or N (C)_1-4Alkyl radical)₂And (4) substitution. In one embodiment, -L-NR¹R²Is C (O)1, 4-diazepanyl.

Another embodiment provides a compound selected from table I A:

TABLE IA

Another embodiment provides a compound of formula I A-iii:

or a pharmaceutically acceptable salt thereof, wherein;

ring A is

J⁵o is H, F, Cl, C_1-4Aliphatic radical, O (C)_1-3Aliphatic group) or OH;

J⁵p is

J⁵p1 is H, C_1-4Aliphatic, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl; wherein J⁵p2 is optionally substituted with 1-2 occurrences of OH or halogen;

J⁵p2 is H, methyl, ethyl, CH₂F、CF₃Or CH₂OH；

J²o is H, CN or SO ₂CH₃；

J²m is H, F, C l or methyl;

J²p is-SO₂(C_1-6Alkyl), -SO₂(C_3-6Cycloalkyl), -SO₂(4-6-membered heterocyclic group), -SO₂(C_1-4Alkyl) N (C)_1-4Alkyl radical)₂or-SO₂(C_1-4Alkyl) - (4-6 membered heterocyclyl), wherein said heterocyclyl comprises 1 heteroatom selected from O, N and S; and wherein said J²p is optionally substituted 1-3 times with halogen, OH or O (C)_1-4Alkyl) substituted.

In some embodiments, ring a is

In other embodiments, ring a is

Another embodiment provides a compound of one of the following tables:

TABLE IA-2

TABLE IA-3

TABLE IVA

TABLE IA-4 (part 1)

TABLE IA-4 (part 2)

Another aspect provides a compound of formula I I,

or a pharmaceutically acceptable salt thereof; wherein

Ring a is a 5-6 membered monocyclic aromatic ring comprising 0-2 heteroatoms selected from N, O or S; ring a is optionally fused to a 5-6 membered aromatic ring containing 0-2 heteroatoms selected from N, O or S;

l is-C (O) -;

R¹is C₁-C₆An alkyl group;

R²is- (C)₂-C₆Alkyl) -Z or a 4-8 membered heterocyclic ring containing 0-2 nitrogen atoms; j wherein the rings are bonded through a carbon atom and are optionally substituted by 1 occurrence^ZSubstitution;

J^Z1is- (X) _t-CN、C₁-C₆Alkyl or- (X)_t-Z；

X is C₁-C₄An alkyl group;

t, p and r are each independently 0 or 1;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

J^Zand J¹Each independently is NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group;

J²is halogen, C optionally substituted by 1-3 fluorine₁-C₂Alkyl or CN;

q is 0, 1 or 2.

In some embodiments, when ring a isR¹When is H; r²Is not provided with

In some embodiments, ring a is a 6-membered ring that is not fused to another ring. In other embodiments, ring a is phenyl, pyridinyl, or pyrimidinyl. In other embodiments, ring a is phenyl.

In some embodiments, R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms. In some embodiments, the heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl,Azepanyl or 1, 4-diazepanyl. In other embodiments, the heterocycle is selected from

In other embodiments, R¹And R²The ring formed being optionally substituted by CH₂Pyrrolidinyl radical, C_1-4Alkyl, N (C)_1-4Alkyl radical)₂Or CH₂CH₂And (3) CN substitution.

In some embodiments, t is 1. In other embodiments, t is 0.

In other embodiments, R¹Is H or C₁-C₆An alkyl group; r²Is- (C)₂-C₆Alkyl) -Z.

In some embodiments, Z is-NR³R⁴Wherein R is³And R⁴Are all C₁-C₂An alkyl group. In other embodiments, R³And R⁴Together with the atoms to which they are attached form a ring selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl. In some embodiments, the ring is pyrrolidinyl or piperidinyl.

In some embodiments, the ring is optionally substituted with 1J^ZAnd (4) substitution. In some embodiments, J is^ZIs C_1-4Alkyl or N (C)_1-4Alkyl radical)₂。

In one embodiment, p is 0, q is 0, -L-NR¹R²Is C (O) pyrrolidinyl, C (O) piperidinyl, C (O) piperazinyl, C (O) azepanyl, C (O)1, 4-diazepanyl, CON (CH)₃)CH₂CH₂N(CH₃)₂Wherein said pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl is optionally substituted with CH₂Pyrrolidinyl radical, C_1-4Alkyl, N (C)_1-4Alkyl radical)₂Or CH₂CH₂And (3) CN substitution.

Another embodiment provides a compound selected from table II.

TABLE II

Another aspect provides a compound of formula III:

or a pharmaceutically acceptable salt thereof; wherein

L is-C (O) -or-SO₂-；

R¹Is H or C₁-C₆An alkyl group;

J^Z1is- (X)_t-CN、C₁-C₆Alkyl or- (X)_t-Z；

X is C₁-C₄An alkyl group;

t, p and r are each independently 0 or 1;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

J^Zand J¹Each independently is NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO(C_1-4Aliphatic group), CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group;

J²is halogen, C optionally substituted by 1-3 fluorine₁-C₂Alkyl or CN;

q is 0, 1 or 2.

In some embodiments, J is ¹Is J as shown in formula I I-I^1aOr J^1b。

In some embodiments, when L is-C (O) -, q is 0, J^1aIs H, J^1bWhen is H or F; when R is¹When is H; r²Is not- (C)_1-4Alkyl) -N (CH)₃)₂(ii) a Or R¹And R²Together are not

In some embodiments, t is 1. In other embodiments, t is 0.

In other embodiments, R¹Is H or C₁-C₆An alkyl group; r²Is- (C)₂-C₆Alkyl) -Z. In some embodiments, Z is-NR³R⁴Wherein R is³And R⁴Are all C₁-C₂An alkyl group. In other embodiments, R³And R⁴Together with the atoms to which they are attached form a ring selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl. In some embodiments, the ring is pyrrolidinyl or piperidinyl.

In some embodiments, the ring is optionally substituted with 1J^ZAnd (4) substitution. In some embodiments, J is^ZIs C_1-4Alkyl or N (C) _1-4Alkyl radical)₂。

In one embodiment, p is 0, q is 0, -L-NR¹R²Is C (O) pyrrolidinyl, C (O) piperidinyl, C (O) piperazinyl, C (O) azepanyl, C (O)1, 4-diazepanyl, C (O) NH-piperidinyl, C (O) NHCH₂CH₂Pyrrolidinyl, C (O) NHCH₂CH₂-piperidinyl, CON (CH)₃)CH₂CH₂N(CH₃)₂Wherein said pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl is optionally substituted with C_1-4Alkyl or N (C)_1-4Alkyl radical)₂And (4) substitution.

Another embodiment provides a compound selected from table III:

TABLE III

Another aspect provides a compound selected from table III-2:

TABLE III-2

Another aspect provides a compound of formula V:

or a pharmaceutically acceptable salt thereof:

wherein

Ring a is an 8-9 membered bicyclic heteroaryl ring having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;

q is a 5-6 membered monocyclic aromatic ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R¹is H or C₁-C₆An alkyl group;

R²is H, C₁-C₆Alkyl, - (C)₂-C₆Alkyl) -Z or a 3-8 membered ring containing 0-2 nitrogen atoms; j wherein the rings are bonded through a carbon atom and are optionally substituted by 1 occurrence ^ZSubstitution;

or R¹And R²Together with the atoms to which they are attached form a 3-8 membered monocyclic or 8-9 membered bicyclic heterocyclic ring containing 1-2 heteroatoms selected from oxygen, nitrogen and sulfur; j wherein said heterocycle is optionally substituted by 1 occurrence^Z1Substitution;

J^Z1is- (X)_t-CN、C₁-C₆Alkyl or- (X)_r-Z¹；

X is C_1-4An alkyl group;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

Z¹is-NR⁵R⁶；

R⁵Is H orC₁-C₂An alkyl group;

R⁶is H or C₁-C₆An alkyl group;

or R⁵And R⁶Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms; j wherein said ring is optionally substituted with 1 occurrence^Z1Substitution;

J¹is halogen, CN or C_1-6Aliphatic radical in which up to 2 methylene units are optionally substituted by O, NR', C (O), S, S (O) or S (O)₂Replacement; said C is_1-6Aliphatic groups are optionally substituted with 1-3 fluorines or CN;

J²is halogen; CN; or C_1-6Aliphatic radical in which up to 2 methylene units are optionally substituted by O, NR', C (O), S, S (O) or S (O)₂Replacement; said C is_1-6Aliphatic groups are optionally substituted with 1-3 fluorines or CN;

J^Zand J^Z1Each independently is NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C _1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO(C_1-4Aliphatic group), CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group;

q and m are each independently 0, 1 or 2;

t, p and r are each independently 0 or 1.

According to one embodiment, ring A is a 9-membered ring. In some embodiments, ring a is a 5-6 bicyclic ring system. The 5-6 bicyclic ring system is a 5-membered ring fused to a 6-membered ring as shown below.

Examples of 5-6 bicyclic ring systems include, but are not limited to, benzimidazolyl, benzoxazolyl, indazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, benzothiazolyl, benzothienyl, indolyl, benzofuranyl, benzotriazolyl, and azaindolyl.

In some embodiments, ring a has 1-2 heteroatoms. In some embodiments, ring a is benzimidazolyl, benzoxazolyl, indazolyl, benzothiazolyl, indolyl, benzotriazolyl, or azaindolyl.

According to another embodiment, ring Q is phenyl or pyridyl. In some embodiments, Q is phenyl.

In some embodiments, p is 1 and ring Q is para by L-NR as shown in formula V-a¹R²And (3) substitution:

in some embodiments, L is C (O) or S (O) ₂. In other embodiments, R¹And R²Are all C_1-4An alkyl group. In other embodiments, R¹And R²Together with the atoms to which they are attached form a 4-7 membered heterocyclic ring containing 1-2 nitrogen atoms. In some embodiments, the heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, and 1, 4-diazepanyl. In some embodiments, the heterocyclyl is 1, 4-diazepanyl.

In other embodiments, ring Q is pyridyl.

In some embodiments, p is 0. In other embodiments, q is 1, J²Is CN.

Another embodiment provides a compound selected from table V:

TABLE V

TABLE V-2

Another embodiment provides a compound of formula VI:

or a pharmaceutically acceptable salt thereof; wherein

l is-C (O) -or-SO₂-；

G is S or O;

R¹is H or C₁-C₆An alkyl group;

or R¹And R ²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms; j wherein said heterocycle is optionally substituted by 1 occurrence^Z1Substitution;

J^Z1is- (X)_t-CN、C₁-C₆Alkyl or- (X)_t-Z；

X is C₁-C₄An alkyl group;

t, p and r are each independently 0 or 1;

z is-NR³R⁴；

R³Is H or C₁-C₂An alkyl group;

R⁴is H or C₁-C₆An alkyl group;

J²is halogen, C optionally substituted by 1-3 fluorine₁-C₂Alkyl radicalOr CN;

q is 0, 1 or 2;

p is 0 or 1.

According to one aspect of the invention, p is 1. In some embodiments, Q is phenyl. In other embodiments, L is-C (O) -. In some embodiments, R¹And R²Together with the atoms to which they are attached form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms. In some embodiments, R¹And R²The heterocyclic ring formed is selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl or 1, 4-diazepanyl. In other embodiments, the heterocyclyl is

According to another aspect of the invention, p is 0, q is 0, -L-NR¹R²Is C (O)1, 4-diazepanyl.

Another embodiment provides a compound selected from table VI:

TABLE VI

Another embodiment provides a compound of formula VI I,

or a pharmaceutically acceptable salt thereof; wherein

Ring A is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally J-linked¹Substitution;

R¹is C₁-C₆An alkyl group;

J¹is C_1-6An alkyl chain wherein 1-2 methylene units are optionally replaced by O, NR x, S or c (o); j. the design is a square¹Optionally substituted with 1-3 occurrences of halogen;

r is H or C_1-4An alkyl group;

J²is halogen, C optionally substituted by 1-3 fluorine₁-C₂Alkyl or CN;

p and q are each independently 0, 1 or 2.

According to another aspect of the invention, ring a is a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring a is pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, triazolyl, thienyl, thiazolyl, thiadiazolyl, furanyl, oxazolyl, or oxadiazolyl. In other embodiments, ring a is pyridyl, pyrazolyl, thiadiazolyl, or thiazolyl, wherein ring a is optionally substituted with halo or C _1-4Alkyl substitution. In some embodiments, ring a is phenyl. In some embodiments, J wherein the phenyl group is 1 occurrence¹And (4) substitution.

In some embodiments, J is¹Is C_1-6An alkyl chain in which 1 methylene unit is replaced by N or O. In other embodiments, J¹Is O (C)_1-4Alkyl) or- (C)_1-4Alkyl) NH (C)_1-4Alkyl groups). In other embodiments, J¹Is- (C)_1-4Alkyl) NH (C)_1-4Alkyl groups).

Another embodiment provides a compound selected from the group consisting of:

TABLE VII

Another embodiment provides a compound selected from table 1.

TABLE I

In some embodiments, the variables are as shown in the compounds disclosed, including the compounds in the tables above.

The compounds of the present invention include those generally described above, and they are further exemplified by the classes, subclasses, and species disclosed herein. The following definitions as used herein apply, unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the periodic Table of the elements, CAS edition, Handbook of Chemistry and Physics, 75 th edition. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorre11, university science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry", fifth edition, Smith, m.b. and March, edited by j, John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

The specific number ranges of atoms as described herein include any integer therein. For example, a group having 1-4 atoms can have 1, 2, 3, or 4 atoms.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, for example as exemplified generally herein or as typified by specific types, subclasses, and classes of the invention. It will be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted. In general, the term "substituted" as used herein, whether before or after the term "optionally" as used herein, means that the hydrogen radical on the specified structure is replaced with a particular substituent. Unless otherwise indicated, an optionally substituted group may bear a substituent at each substitutable position of the group, and when more than one position on any given structure is substituted with more than one substituent selected from the particular group, the substituents may be the same or different at each position. The combination of substituents contemplated by the present invention is preferably a combination that results in the formation of a stable or chemically feasible compound.

Unless otherwise indicated, a substituent attached by a bond drawn from the center of a ring means that the substituent may be bonded at any position of the ring. For example, in example i below, J ¹Can be bonded at any position on the pyridyl ring. In the case of bicyclic rings, the bond drawn through the two rings indicates that the substituent may be bonded from any position on the bicyclic ring. For example, in example ii below, J¹May be bonded to a 5-membered ring (e.g., at the nitrogen atom) and a 6-membered ring.

The term "stable" as used herein refers to compounds that do not substantially change when subjected to the conditions for their production, detection, and preferably for their recovery, purification, and for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically useful compound is one that does not substantially change when held at a temperature of 40 ℃ or less for at least one week in the absence of moisture or other chemically reactive conditions.

The term "aliphatic" or "aliphatic group" as used herein refers to a straight (i.e., unbranched), branched, or cyclic substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation, which has a single point of attachment to the remainder of the molecule.

Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. Aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups may be straight or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl.

The term "cycloaliphatic radical" (or "carbocycle" or "carbocyclyl") refers to a monocyclic C₃-C₈C of hydrocarbons or bicyclic rings₈-C₁₂A hydrocarbon, which is fully saturated or contains one or more units of unsaturation, but which is not aromatic, having a single point of attachment to the remainder of the molecule, wherein any individual ring in said bicyclic ring system has from 3 to 7 members. Examples of alicyclic groups include, but are not limited to, cycloalkyl and cycloalkenyl. Specific examples include cyclohexyl, cyclopropenyl and cyclobutyl.

The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein means a non-aromatic monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle", "heterocyclyl", or "heterocyclic" group has 3-14 ring members, where one or more ring members are atoms independently selected from oxygen, sulfur, nitrogen, or phosphorus, and the rings in the system each contain 3-7 ring members.

Examples of heterocycles include, but are not limited to, 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyrazinyl, 2-tetrahydropyrazinyl, 3-tetrahydropyrazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 3-morpholinyl, and optionally substituted, 5-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzothiolane, benzodithiane, and 1, 3-dihydro-imidazol-2-one.

Cyclic groups (e.g., alicyclic and heterocyclic) may be linearly fused, bridged, or spiro.

The term "heteroatom" means one or more oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen; heterocyclic substitutable nitrogen, e.g. N (as on 3, 4-dihydro-2H-pyrrolyl), NH (as on pyrrolidinyl) or NR⁺(e.g., on an N-substituted pyrrolidinyl group)).

The term "unsaturated" as used herein means a moiety having one or more units of unsaturation. As known to those skilled in the art, the unsaturated groups may be partially unsaturated or fully unsaturated. Examples of partially unsaturated groups include, but are not limited to, butene, cyclohexene, and tetrahydropyridine. The fully unsaturated groups may be aromatic, trans-aromatic or non-aromatic. Examples of fully unsaturated groups include, but are not limited to, phenyl, cyclooctatetraene, pyridyl, thienyl, and 1-methylpyridin-2 (1H) -one.

The term "alkoxy" or "alkylthio" as used herein means an alkyl group as defined above attached through an oxygen ("alkoxy") or sulfur ("alkylthio") atom.

The terms "haloalkyl", "haloalkenyl"),"Haloaliphatic" and "haloalkoxy" mean alkyl, alkenyl, or alkoxy, which in this regard may be substituted with one or more halogen atoms. The term includes perhaloalkyl groups, e.g. -CF₃and-CF₂CF₃。

The terms "halogen", "halo" and "hal" mean F, Cl, Br or I.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" means monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic and wherein the rings in the system each contain 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring".

The term "heteroaryl" used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy" means monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic, at least one ring in the system contains one or more heteroatoms and wherein the rings in the system each contain 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic group". Examples of heteroaryl rings include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, purinyl, pyrazinyl, 1, 3, 5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

It is to be understood that the term "heteroaryl" includes some types of heteroaryl rings that exist in equilibrium between two different forms. More specifically, for example, the class of hydrogenated pyridines and pyridones (also hydroxypyrimidines and pyrimidinones) is intended to be included within the definition of "heteroaryl".

As used herein, the terms "protecting group" and "protecting group" are used interchangeably and refer to a reagent used to temporarily block a desired functional group on one or more compounds having multiple reactive sites. In some embodiments, the protecting group has one or more, or preferably all, of the following characteristics: a) is selectively added to the functional group in good yield to give a protected substrate; b) (ii) a stable reaction at one or more other reaction sites; and c) is selectively removed in good yield by a reagent that does not attack the regenerating, deprotected functional group. As will be appreciated by those skilled in the art, in some cases, these agents do not attack other reactive groups on the compound. In other cases, these reagents may also react with other reactive groups on the compound. Examples of protecting groups are described in detail in Greene, t.w., Wuts, P.G, "Protective group Organic Synthesis", 3 rd edition, John Wiley & Sons, New York: 1999 (and other versions of this document), which is incorporated herein by reference in its entirety. The term "nitrogen protecting group" as used herein means a reagent used to temporarily block one or more desired nitrogen reactive sites on a polyfunctional compound. Preferred nitrogen protecting groups also have the characteristics typical of the protecting groups described above and some typical nitrogen protecting groups are also described in detail in Greene, t.w., Wuts, P.G, "protective group in Organic Synthesis", 3 rd edition, John Wiley & Sons, New York: 1999 (and other versions of this document), which is incorporated herein by reference in its entirety to Greene, T.W., Wuts, P.G, "protective group in Organic Synthesis", 3 rd edition, John Wiley & Sons, New York: 1999 chapter 7, which is incorporated herein by reference in its entirety.

In some embodiments, the methylene units of the alkyl or aliphatic chain are optionally replaced by additional atoms or groups. Examples of such atoms or groups include, but are not limited to, nitrogen, oxygen, sulfur, -C (o) -, -C (═ N-CN) -, -C (═ NR) -, -C (═ NOR) -, -SO-, and-SO₂-. These atoms or groups may be combined into larger groups. Examples of such larger groups include, but are not limited to, -OC (O) -, -C (O) CO-, -CO-₂-、-C(O)NR-、-C(＝N-CN)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-, -NRC (O) NR-, -OC (O) NR-and-NRSO₂NR-, wherein R is, for example, H or C_1-6An aliphatic group. It is understood that these groups may be bonded via single, double or triple bonds to synthesize the methylene units of the aliphatic chain. An optionally substituted example of bonding to the aliphatic chain via a double bond (for that matter the nitrogen atom) may be-CH₂CH＝N-CH₃. In some cases, especially at the terminus, the optional substitution may be bonded to the aliphatic group through a triple bond. An example of this may be CH₂CH₂CH₂C ≡ N. It is understood that in this case the terminal nitrogen is not bonded to another atom.

It is also to be understood that the term "methylene unit" may also refer to a branched or substituted alkylene unit. For example, in isopropyl [ -CH (CH)₃)₂]On the part, replacement of the nitrogen atom (e.g. NR) of the first said "methylene unit" may yield dimethylamine [ -N (CH) ₃)₂]. For example, in such a case, one skilled in the art would understand that the nitrogen atom does not have any other atoms bonded to it, and the "R" from the "NR" is not present in this case.

Optional substitutions may form chemically stable compounds unless otherwise indicated. Optional substitutions may occur within the strand and/or at either end of the strand; i.e. at the point of attachment and/or also at the end. The two optional substitutions may also be adjacent to each other within the chain, provided that it results in a chemically stable compound. E.g. C₃The aliphatic group may optionally be replaced by 2 nitrogen atoms to form-C-N ≡ N. Optional substitutions may also completely replace all carbon atoms in the chain. E.g. C₃Aliphatic groups may be optionally replaced by-NR-, -C (O) -and-NR-to form-NRC (O) NR- (urea).

Unless otherwise indicated, if a substitution occurs at a terminus, the substituting atom is bonded to a hydrogen atom on the terminus. For example, if-CH₂CH₂CH₃Optionally substituted by-O-, the resulting compound may be-OCH₂CH₃、-CH₂OCH₃or-CH₂CH₂And (5) OH. It is understood that if the terminal atom does not contain any free valence electrons, then no hydrogen atom (e.g., -CH) is required at the terminal₂CH₂CH ═ O or-CH₂CH₂C≡N)。

Unless otherwise indicated, a structure described herein is also intended to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, conformational, and rotational) forms of the structure. For example, the respective R and S configurations of the asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are encompassed by the present invention. As will be appreciated by those skilled in the art, substituents may be free to rotate about any rotatable bond. For example, draw to The substituents also represent

Thus, single stereochemical isomers and mixtures of enantiomers, diastereomers, geometric isomers, conformers and rotamers of the compounds of the present invention are within the scope of the present invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In addition, unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of an enriched isotopic atom or atoms. For example, except that hydrogen is replaced by deuterium or tritium or that carbon is enriched¹³C-or¹⁴In addition to carbon substitution for C, compounds having the structure of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in bioassays.

Pharmaceutically acceptable salts

The compounds of the invention may be present in free form for use in therapy or, if appropriate, as pharmaceutically acceptable salts.

By "pharmaceutically acceptable salt" is meant any non-toxic salt of a compound of the present invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof. The term "an inhibitory active metabolite or residue thereof" as used herein means that the metabolite or residue thereof is also an ATR protein kinase inhibitor.

Pharmaceutically acceptable salts are well known in the art. For example, s.m. berge et al describe pharmaceutically acceptable salts in j.pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. The acid addition salt may be prepared by the following steps: 1) reacting the purified compound in free form with a suitable organic or inorganic acid; and 2) isolating the salt thus formed.

Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, glycolates, gluconates, glycolates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamonates (palmoates), pectates, pectinates, benzenesulfonates, glycolates, glycol, Persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonate, undecanoates, valeric acid salts, and the like.

The base addition salt may be prepared by the following steps: 1) reacting the purified compound in acid form with a suitable organic or inorganic base; and 2) isolating the salt thus formed. Salts derived from suitable bases include alkali metals (e.g., sodium, lithium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, and N⁺(C_1-4Alkyl radical)₄And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-or oil-soluble or dispersible products can be obtained by this quaternization.

Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, ethylformate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate, as appropriate. Other acids and bases (while themselves pharmaceutically acceptable) may be used in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid or base addition salts.

Abbreviations

The following abbreviations are used:

compound application

One aspect of the invention provides compounds for inhibiting ATR kinase. These compounds have the formula I:

or a pharmaceutically acceptable salt thereof;

wherein

R¹Is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said monocyclic aryl or heteroaryl ring is optionally fused to another ring to form an 8-10 membered bicyclic aryl or heteroaryl ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r¹Each optionally substituted by 1-5J¹Substituted by groups;

R²is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said monocyclic aryl or heteroaryl ring is optionally fused with another ring to form an 8-10 membered bicyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r²Each optionally substituted by 1-5J²Substituted by groups;

l is-C (O) NH-or-C (O) N (C)_1-6Alkyl) -;

n is 0 or 1;

J¹and J²Each independently halogen, -CN, -NO₂、-V¹-R or- (V)²)_m-Q；

V¹Is C_1-10An aliphatic chain in which 0 to 3 methylene units are optionally and independently O, NR', S, C (O), S (O) or S (O)₂Replacement; v¹J optionally occurring 1-6 times^V1Substitution;

V²is C_1-10An aliphatic chain in which 0 to 3 methylene units are optionally and independently O, NR', S, C (O), S (O) or S (O)₂Replacement; v²J optionally occurring 1-6 times^V2Substitution;

m is 0 or 1;

q is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 9-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is optionally substituted with 0-5J ^QSubstitution;

J^V1or J^V2Each independently of the others being halogen, CN, NH₂、NO₂、C_1-4Aliphatic radical, NH (C)_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂、OH、O(C_1-4Aliphatic group), CO₂H、CO₂(C_1-4Aliphatic group), C (O) NH₂、C(O)NH(C_1-4Aliphatic radical), C (O) N (C)_1-4Aliphatic radical)₂、NHCO(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical) CO (C)_1-4Aliphatic group), SO₂(C_1-4Aliphatic group), NHSO₂(C_1-4Aliphatic radical) or N (C)_1-4Aliphatic group) SO₂(C_1-4Aliphatic radical), wherein said C_1-4Aliphatic groups are optionally substituted with halogen;

r is H or C_1-6Aliphatic radicalWherein said C is_1-6NH in which the aliphatic radical is optionally present 1 to 4 times₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), CO (C)_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4Aliphatic group substitution;

J^Qeach independently is halogen, oxo, CN, NO₂X-R or- (X)_p-Q⁴；

p is 0 or 1;

x is C_1-10An aliphatic group; wherein said C_1-61-3 methylene units of an aliphatic radical being optionally substituted by-NR, -O-, -S-, C (O), S (O)₂Or S (O) substitution; NH wherein X is optionally and independently present 1 to 4 times₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO(C_1-4Aliphatic group), CO₂H、CO₂(C_1-4Aliphatic group), C (O) NH₂、C(O)NH(C_1-4Aliphatic radical), C (O) N (C) _1-4Aliphatic radical)₂、SO(C_1-4Aliphatic group), SO₂(C_1-4Aliphatic group), SO₂NH(C_1-4Aliphatic group), SO₂N(C_1-4Aliphatic radical)₂、NHC(O)(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical) C (O) (C_1-4Aliphatic radical), wherein said C is_1-4Aliphatic groups are optionally substituted with 1-3 occurrences of halogen;

In one embodiment, R¹Is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said monocyclic aryl or heteroaryl ring is optionally fused with another ring to form an 8-10 membered bicyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r ¹Each optionally substituted by 1-5J¹Substituted by groups;

J^V1or J^V2Each independently is NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), CO (C)_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group;

J^Qeach independently halogen, NO₂CN or C_1-6Aliphatic radical in which up to 1 methylene unit is optionalGround coating NR', O, S, CO₂、CONR′、SO、SO₂、SO₂NR′、OCO、NR′CO、NR′COO、NR′SO、NR′SO₂、NR′SO₂NR ', OCONR' or NR 'CONR'; wherein said C_1-6The aliphatic group is optionally substituted with 1-4 substituents selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), CO (C)_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4An aliphatic group.

In some embodiments, R²J optionally occurring one or two times ²And (4) substitution. In other embodiments of the present invention, the substrate may be,

in some embodiments, R²Is a 5-6 membered monocyclic aromatic ring. In some embodiments, R²Is a 6-membered aromatic ring. In other embodiments, R²Is phenyl or pyridyl. In other embodiments, R²Is phenyl.

R²Optionally substituted by 1-5J²And (4) substituting the group. In some embodiments, 1-3J²Substituted with radicals, in other embodiments, 1-2J²And (4) substituting the group. In another embodiment, R²J by 0 or 1 occurrence²And (4) substitution. In some embodiments, J is²Is- (V)²)_m-Q or V¹-R; wherein

V¹And V²Each independently is C_1-6An aliphatic chain in which 0 to 3 methylene units are optionally substituted by O, NR', S, C (O), S (O) or S (O)₂Replacement; wherein the first or second methylene group remote from the point of attachment is replaced by C (O), S (O) or S (O)₂S or O;

m is 1;

r is H; and is

Q is a 5-7 membered monocyclic ring containing 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; wherein said Q is optionally substituted with 1-3 occurrences of halogen, C_1-3Alkyl, CN, OH, O (C)_1-3Alkyl), NH₂、NH(C_1-3Alkyl group), N (C)_1-3Alkyl radical)₂Or CO (C)_1-3Alkyl) substituted.

In some embodiments, Q is a 5-6 membered monocyclic ring.

According to another embodiment, n is 0.

In some embodiments, n is 0 and R is ¹Is a 5-6 membered monocyclic aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 9-10 membered bicyclic aromatic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R is¹Each optionally substituted by 1-5J¹And (4) substituting the group.

In some embodiments, R¹Is benzothiazole, oxadiazole, benzoxazole, triazole, thiadiazole or isoxazole. In other embodiments, R¹Is benzimidazole, benzothiazole (benzothiazoles), oxadiazole, isoxazole or triazole. In some embodiments, R¹Is a benzimidazole. In other embodiments, R¹Is isoxazole.

R¹Optionally substituted by 1-5J¹And (4) substituting the group. In some embodiments, 1-3J¹Substituted with radicals, in other embodiments, 1-2J¹And (4) substituting the group. In some embodiments, J is¹Is halogen, CN, NO₂or-V¹-R. In other embodiments, J¹Is halogen, CN, C_1-6Alkyl, OR, SR, NR "R, C (O) R, C (O) OR, C (O) NR" R, S (O)₂R or S (O) R. In other embodiments, J¹Is optionally substituted by NH₂、C_1-4Alkyl, thiophene or CH₂NH₂A substituted phenyl group.

In some embodiments, R²Is a 5-6 membered monocyclic aromatic ring. In some embodiments, R²Is a 6-membered aromatic ring. In other embodiments, R ²Is phenyl or pyridyl. In other embodiments, R²Is phenyl.

In another embodiment, J²is-V¹-R or- (V)²)_m-Q; wherein V¹And V²Is O, NR', -CO-or-SO₂-; q is a 5-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N or O; j. the design is a square^V1And J^V2Is a halogen. In another embodiment, J²Is SO₂CH₃Morpholinyl, CH₂OH, C (O) - (morpholinyl), C (O) NH (C)_1-4Alkyl) OH, piperazinyl, CN, CH₂NHC(O)CH₃Halogen, C (O) NH (C)_1-4Alkyl) pyrrolidinyl or SO₂(pyrrolidinyl).

In some embodiments, R²Is phenyl or pyridyl.

In some embodiments, J is²Is SO₂(C_1-4Alkyl groups).

In one embodiment of the process of the present invention,

n is 0;

R¹is benzimidazole, benzothiazole, benzoxazole, oxadiazole, isoxazole, thiadiazole or triazole;

J¹is halogen, CN, NO₂or-V¹-R；

R²Is phenyl or pyridyl;

J²is- (V)²)_m-Q or-V¹-R；

m is 1;

V¹and V²is-SO₂-, -O-, -NR-, or-CO-;

q is a 5-6 membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen or oxygen; and is

R is H or C_1-6Alkyl radical, wherein said C_1-6Alkyl is optionally substituted with 1-4 halogens.

According to another embodiment, n is 1.

In some embodiments, R¹Is phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperonyl, indolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzothienyl (i.e., benzothienyl), benzoxazolyl, pyrrolopyrimidinyl, pyrrolopyridyl, azaindazolyl (azaindazolyl), or azaindolyl (azaindolyl). In other embodiments, R ¹Is phenyl, pyridyl, pyrimidyl, piperonyl or indole. In other embodiments, R¹Is phenyl.

R¹Optionally substituted by 1-5J¹And (4) substituting the group. In some embodiments, 1-3J¹Substituted with radicals, in other embodiments, 1-2J¹And (4) substituting the group. In some embodiments, J is¹Is C_1-6Alkyl, CN, halogen, OR, NR' R, SR, COR, CO₂R、CONR″R、SOR、SO₂R、S(O)₂NR″R、OCOR、NRC(O)R、NRCOOR、NRSOR、NRSO₂R、NRSO₂NR "R, OCONR" R or NRCONR "R; a 4-6 membered fully saturated monocyclic ring containing 0-2 heteroatoms selected from oxygen, nitrogen or sulfur. In other embodiments, J¹Is C_1-6Alkyl, CN, halogen, OR, NR "R, CONR" R, S (O)₂NR' R, NC (O) R or pyrrolidinyl.

In some embodiments, R²Is phenyl, pyridyl, pyrimidinyl, indole, furanyl, pyrazole, thiophene, tetrahydropyran, or indazole. R²Optionally substituted by 1-5J²And (4) substituting the group. In some embodiments, 1-3J²Substituted with radicals, in other embodiments, 1-2J²And (4) substituting the group. In some embodiments, J is²Is halogen, CN, NR' R, C_1-6Alkyl, OR, SO₂R、NHSO₂R, COOR, CONR' R, morpholinyl, -V¹-R or- (V)²)_m-Q, wherein

V¹And V²Is CO, -CONR "-, -CONR" - (C)_1-4Alkyl) -, -CONR' - (C)_1-4Alkyl) -OCH ₂-、-CONR″-(C_1-4Alkyl) -N (CH)₃)-；

R is H or C_1-4An alkyl group; and is

Q is 1, 4-diazepanyl, azetidinyl optionally substituted by OMe, optionally substituted by C_1-4Alkyl, 4-CH₂OH、CONH₂Pyrrolidinyl, OH or CH₂-pyrrolidinyl-substituted piperidinyl; optionally substituted by CH₂CH₂CN、CH₃、COCH₃Substituted piperazinyl, pyrrolidinyl optionally substituted with dimethylamino, tetrahydropyran, C optionally substituted with OH_3-10A cycloalkyl group.

In other embodiments, J²Is SO₂CH₃、NHSO₂CH₃、CN、OH、OCH₃、F、N(CH₃)₂、NHSO₂CH₃、CF₃、C_1-6Alkyl, CO (1, 4-diazepanyl), COOH, CONH₂、CON(CH₃)₂CO (azetidinyl), CON (CH)₃)(C_1-4Alkyl) OCH₃、CONH(C_1-4Alkyl) piperazinyl, CONH (C)_1-4Alkyl) piperidinyl, CONH-tetrahydropyran, CON (methylpiperidinyl), CO (piperidinyl), CONH-cyclopropyl, CO (morpholinyl), CON (CH)₃)-(C_1-4Alkyl) -N (CH)₃)₂CO (piperazinyl), CONH- (C)_1-4Alkyl) -pyrrolidinyl, CONH- (C)_1-4Alkyl) -piperidinyl, CONH- (C)_1-4Alkyl) -tetrahydropyranyl, morpholinyl, CO (pyrrolidinyl), CO (piperidinyl), CO (pyrrolidinyl), CH₂-pyrrolidinyl or CONH (cyclohexyl), wherein said J²Optionally is covered with C_1-4Alkyl, CONH₂Pyrrolidinyl, OH, O (C)_1-4Alkyl), NH₂、NH(C_1-4Alkyl group), N (C)_1-4Alkyl radical)₂、-(C_1-4Alkyl) -CN, - (C)_1-4Alkyl) -OH, - (C)_1-4Alkyl) -N (C)_1-4Alkyl radical)₂Or CO (C)_1-4Alkyl) substituted.

In some embodiments of the present invention, the substrate is,

n is 1;

R¹is phenyl;

R²is phenyl, pyridyl, indole, furyl, pyrazole, thiophene, tetrahydropyran or indazole;

J²is halogen, CN, NR' R, C_1-6Alkyl, OR, SO₂R、NHSO₂R, COOR, CONR' R, morpholinyl, -V¹-R or- (V)²)_m-Q, wherein

m is 1;

V¹and V²Is CO, -CONR- (C)_1-4Alkyl) -, CONR- (C)_1-4Alkyl) -OCH₂-or-CONR- (C)_1-4Alkyl) -N (CH)₃)-；

R is H or C_1-4An alkyl group; and is

Q is 1, 4-diazepanyl, azetidinyl optionally substituted by OMe, optionally substituted by C_1-4Alkyl, 4-CH₂OH、CONH₂Pyrrolidinyl, OH or CH₂-pyrrolidinyl-substituted piperidinyl; optionally substituted by CH₂CH₂CN、CH₃、COCH₃Substituted piperazinyl, pyrrolidinyl optionally substituted with dimethylamino, tetrahydropyran, C optionally substituted with OH_3-10A cycloalkyl group; and is

J¹Is C_1-6Alkyl, CN, halogen, OR, NR' R, SR, COR, CO₂R、CONR″R、SOR、SO₂R、S(O)₂NR″R、OCOR、NRC(O)R、NRCOOR、NRSOR、NRSO₂R、NRSO₂NR "R, OCONR" R or NRCONR "R; a 4-6 membered fully saturated monocyclic ring containing 0-2 heteroatoms selected from oxygen, nitrogen or sulfur.

In other embodiments of the present invention, the substrate may be,

n is 0;

R¹is benzimidazole, benzothiazole, oxadiazole, isoxazole or triazole;

J¹is halogen, CN, NO₂or-V¹-R；

R²Is phenyl or pyridyl;

J²is- - (V)²)_m-Q or-V¹-R；

m is 1;

V¹and V²is-SO ₂-, -O-, -NR "-, or-CO-;

In other embodiments, the compound is selected from table 1 (above).

One aspect of the invention provides compounds that are inhibitors of ATR kinase, and thus their use in treating or lessening the severity of a disease, condition or disorder in which ATR is implicated.

Another aspect of the invention provides compounds for use in the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include proliferative or hyperproliferative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer and myeloproliferative diseases.

In some embodiments, the compound is selected from compounds of formula I, II, III, IV, IA, IIA, IIIA, IVA, IA-I, IA-II, IA-III, V, VI and VII.

The term "cancer" includes, but is not limited to, the following cancers: oral cavity, lip, tongue, mouth, pharynx;heart and heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung (lung): bronchogenic carcinoma (squamous cell or epidermoid carcinoma, poorly differentiated small cell carcinoma, poorly differentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenocarcinoma, sarcoma, lymphoma, hamartoma, mesothelioma;gastrointestinal tract: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, pancreatic tumor), small or small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large or large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon-rectum, colorectal; a rectum part,Urogenital tract: kidney (adenocarcinoma, Wilms' tumor [ nephroblastoma ]]Lymphoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); _{Liver disease}: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract;bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chondrosarcoma (osteoochronofroma), benign chondroma, chondroblastoma, chondrosamyxofibroma, osteoid osteoma, and giant cell tumor;nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, etc)Tumor, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell [ pinealoma ]]Glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);gynaecology department: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma [ serous cystadenocarcinoma, myxocystadenocarcinoma, nontypal carcinoma) ]Granulosa-thecoma, sertoli cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast;skin(s): malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, melanoma, and combinations thereof,Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; andadrenal gland: neuroblastoma.

Thus, the term "cancer cell" as provided herein includes cells affected by any of the above identified diseases. In some embodiments, the cancer is selected from colorectal cancer, thyroid cancer, or breast cancer.

The term "myeloproliferative disease" includes diseases such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, systemic mastocytosis, and hematopoietic committed stem cell disease, particularly Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Acute Promyelocytic Leukemia (APL), and Acute Lymphocytic Leukemia (ALL).

Pharmaceutically acceptable derivatives or prodrugs

In addition to the compounds of the present invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of the present invention may also be used in compositions for the treatment or prevention of the diseases identified herein.

The compounds of the present invention may also be present as pharmaceutically acceptable derivatives.

A "pharmaceutically acceptable derivative" is an adduct or derivative that upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound or metabolite or residue thereof as otherwise described herein. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.

By "pharmaceutically acceptable derivative or prodrug" is meant any pharmaceutically acceptable ester, salt of an ester or other derivative of a compound of the invention or salt thereof which is capable of providing, directly or indirectly, a compound of the invention or an inhibitory metabolite or residue thereof upon administration to a recipient. Particularly advantageous derivatives or prodrugs are those that increase the bioavailability of the compounds of the invention when such compounds are administered to a patient (e.g., by oral administration of the compounds to facilitate easier absorption into the blood) or to facilitate delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of the present invention include, but are not limited to, esters, amino acid esters, phosphates, metal salts, and sulfonates.

Pharmaceutical composition

The invention also provides compounds and compositions useful as inhibitors of ATR kinase.

One aspect of the invention provides a pharmaceutically acceptable composition comprising any of the compounds as described herein and optionally a pharmaceutically acceptable carrier, adjuvant or vehicle.

Pharmaceutically acceptable carriers, adjuvants or vehicles as used herein include any and all solvents, diluents or other liquid carriers, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, 16 th edition, e.w. martin (Mack Publishing co., Easton, Pa., 1980) describe various carriers and known preparative techniques used in formulating pharmaceutically acceptable compositions. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., by producing any undesirable biological effect or by interfering in a deleterious manner with any other component of the pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the invention.

Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

Combination therapy

Another aspect of the invention relates to a method of treating cancer, the method comprising administering to a subject in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent. In some embodiments, the method comprises administering the compound, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent sequentially or together.

In some embodiments, the additional therapeutic agent is an anti-cancer drug. In other embodiments, the additional therapeutic agent is a DNA-damaging agent. In other embodiments, the additional therapeutic agent is selected from radiation therapy, chemotherapy, or other active agents typically used in combination with radiation therapy or chemotherapy, such as radiosensitizers and chemosensitizers.

As will be appreciated by those skilled in the art, a radiosensitizer is an active agent that can be used in conjunction with radiation therapy. Radiosensitizers work in different ways, including, but not limited to, sensitizing cancer cells to radiation therapy, acting synergistically with radiation therapy to provide improved synergy, acting synergistically with radiation therapy or preventing damage to surrounding healthy cells from radiation therapy. Similarly, a chemosensitizer is an active agent that can be used in combination with chemotherapy. Similarly, chemosensitizers act in different ways, including, but not limited to, making cancer cells more sensitive to chemotherapy, chemotherapy acting synergistically together to provide improved synergy, acting in concert with chemotherapy or preventing damage to surrounding healthy cells from chemotherapy.

Examples of DNA-damaging agents that may be used in combination with the compounds of the present invention include, but are not limited to:platinum medicine(platingagents) such as cisplatin, nedaplatin, satraplatin and other derivatives;topo I inhibitorsSuch as topotecan, irinotecan/SN 38, rubitecan and other derivatives;antimetabolitesSuch as the folate classes (methotrexate, pemetrexed and the like); purine antagonists and pyrimidine antagonists (thioguanine, fludarabine, cladribine, cytarabine, and the like),Gemcitabine, 6-mercaptopurine, 5-fluorouracil (5FU) and the like);alkylating agentSuch as nitrogen mustards (cyclophosphamide, melphalan, chlorambucil, mechlorethamine, ifosfamide, and the like); nitrosoureas (e.g., carmustine); triazenes (dacarbazine, temozolomide); alkyl sulfonates (e.g., busulfan); procarbazine and aziridines;antibioticSuch as hydroxyurea, anthracyclines (doxorubicin, daunorubicin, epirubicin, and other derivatives); anthracenediones (mitoxantrone and the like); streptomycetaceae (bleomycin, mitomycin C, actinomycin); and ultraviolet light.

Other therapies or anti-cancer agents that may be used in conjunction with the active agents of the present invention include surgery, radiation therapy (but in several examples, gamma ray, neutron beam radiation, electron beam radiation, proton therapy, brachytherapy, and systemic radioisotopes, etc.), endocrine therapy, biological response modifiers (interferons, interleukins, and Tumor Necrosis Factor (TNF), etc.), hyperthermia and cryotherapy, agents that attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic agents including, but not limited to, the DNA damaging agents cited herein, spindle poisons (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), nitrosoureas (carmustine, lomustine), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen ), and others, Leuprorelin, flutamide and megestrol), Gleevec ^TMDoxorubicin, dexamethasone, and cyclophosphamide.

The compounds of the invention may also be used to treat cancer in combination with any of the following therapeutic agents: abarelix (Plenaxis)) (ii) a AldesleukinAldesleukinArlizumabAliretin A acidAllopurinolAltretamineAmifostineAnastrozoleArsenic trioxideAsparaginaseAzacitidineBevacizumabBexarotene capsuleBexarotene gelBordetecinBortezomibVeinBusulfan (Busulfan)Busulfan for oral cavityCascadendrosteroneCapecitabineCarboplatinCarmustineCarmustineCarmoustine (Gliadel) using polifeprosan 20 implant) (ii) a CelecoxibCetuximabChlorambucilCis-platinumCladribineClofarabineCyclophosphamideCyclophosphamide (Cytoxan)) (ii) a Cyclophosphamide (Cytoxan)) (ii) a Cytosine arabinoside (Cytosar-) (ii) a Cytarabine liposomeDacarbazine (DTIC-) (ii) a Actinomycin D (dactinomycin), actinomycin DDarbepoetin alphaDaunorubicin liposomeDaunorubicin, daunorubicinDaunorubicin, daunorubicinDiniil interleukin 2DexrazoxaneDocetaxelDoxorubicin (Adriamycin)) (ii) a DoxorubicinDoxorubicin (Adriamycin PFS)) (ii) a Doxorubicin liposome Methylpropionic acid androsteroneMethylpropionic acid androsteroneElliott's B lysostaphin (Elliott's B)) (ii) a EpirubicinAlfa iboteneErlotinibEstramustinePhosphoric acidEtoposideEtoposide, VP-16ExemestaneFilgrastimFloxuridine (in artery)FludarabineFluorouracil, 5-FUFulvestrantGefitinibGemcitabineGemtuzumab ozolomicinGoserelin acetate (Zoladex)) (ii) a Goserelin acetateHistrelin acetate (Histrelin)) (ii) a HydroxyureaIbritumomab tiuxetanIdarubicin (Idarubicin)Isocyclophosphamide (ACS)Imatinib mesylateAlpha interferon-2 a (Roferon)) (ii) a Interferon alpha-2 b (Intron)) (ii) a IrinotecanLenalidomideLetrozoleCalcium folinateLeuprorelin acetateLevoimidazoleLomustine, CCNUmeclorethamine, mechlorethamineMegestrol acetateMelphalan, L-PAMMercaptopurine, 6-MPMesna sodiumMesna (Mesnex)) (ii) a Methotrexate (methotrexate)) (ii) a MethoxsalenMitomycin CMitotane (TM)MitoxantroneNonoslone phenylpropionate (Durabolin-) (ii) a NelarabineRumomab (Rumex)Interleukin, oproprilOxaliplatinPaclitaxelPaclitaxelPaclitaxel protein conjugate particlesPaliferminDisodium Aminohydroxy diphosphateAdding enzyme (Adagen (Pegademase Bovine) ) (ii) a Pemen winter enzymePefei shi pavilionPemetrexed disodiumPentostatinPipobromanPrecamycin, PrecamycinPorfimer sodiumProcarbazineQuinacrineLabulinaseRituximabSaggestanSaggestanSorafenibChain zotardSunitinib maleateTalcum powderTamoxifenTemozolomideTeniposide, VM-26Testicle cheeseThioguanine, 6-TG (thioguanine)) (ii) a ThiotepaTopotecanToremifeneTositumomabtositumomab/I-131 tositumomabTrastuzumabRetinoic acid, ATRAUracil mannomustine (Uracil Mustard)) (ii) a ValrubicinVinblastineVincristineVinorelbineZoledronic acid saltsAnd Volinostat

For a review discussion of the latest data on cancer therapy, see http:// www.nci.nih.gov/, a list of FDA approved tumor drugs, see http:// www.fda.gov/cd/cancer/drug frame. htm and the Merck Manual, 17 th edition 1999, the entire contents of which are incorporated herein by reference.

Administration of the composition to a subject

The ATR kinase inhibitor, or a pharmaceutically acceptable salt thereof, may be formulated into a pharmaceutical composition for administration to an animal or human. These pharmaceutical compositions comprising an ATR inhibitor in an amount effective to treat or prevent the diseases or conditions described herein and a pharmaceutically acceptable carrier are another embodiment of the present invention.

The exact amount of the compound required for treatment will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular active agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in unit dosage forms that are easy to administer and are uniform in dosage. The expression "unit dosage form" as used herein means physically discrete units of active agent suitable for the patient to be treated. However, it will be understood that the total daily dosage of the compounds and compositions of the present invention is determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular patient or organism depends on various factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination or concomitantly with the particular compound employed, and the like, are well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal and most preferably a human.

In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents. For example, chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of the invention to treat proliferative diseases and cancer. Examples of known active agents that can be combined with these compositions are set forth in the "combination therapy" section above and also throughout the specification. Some embodiments provide for the use of simultaneous, separate or sequential combined preparations.

Modes of administration and dosage forms

The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally, and as an oral or nasal spray, depending on the severity of the infection to be treated. In some embodiments, the compounds of the present invention may be administered orally or parenterally, once or more times daily, at dosage levels of from about 0.01mg/kg to about 50mg/kg, and preferably from about 1mg/kg to about 25mg/kg, of the subject's body weight per day to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example, sterile injectable aqueous or oleaginous suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable carriers or solvents that can be used are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

In order to prolong the effect of the compounds of the invention, it is often necessary to slowly absorb the compounds injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound will then depend on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delaying absorption of a parenterally administered compound form may be achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot dosage forms are prepared which include a matrix of microcapsules of the compound formed in a biodegradable polymer such as polylactic-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injections can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository waxes which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coating materials well known in the pharmaceutical formulating art. They may optionally contain opacifying agents, and may also be of a composition: they release one or more active ingredients only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active compound may also be present in microcapsules with one or more of the above excipients. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coating materials well known in the pharmaceutical formulating art. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. These dosage forms may also, for example, contain, as is common practice, other substances than inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents, and may also be of a composition: they release one or more active ingredients only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the present invention. Furthermore, the present invention encompasses the use of transdermal patches, which have the additional advantage of controllably delivering the compound to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by implantation of a depot. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The compositions are preferably administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the invention may be an aqueous or oleaginous suspension. These suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, for example olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers which are commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, carriers that are commonly used include, but are not limited to, lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the active agent with a suitable non-irritating excipient. The suitable non-irritating excipients are solid at room temperature but liquid at the rectal temperature and therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered topically, especially where the target of treatment includes areas or organs readily accessible by topical application, including ocular, dermatological, or lower intestinal diseases. Suitable topical formulations for each of these areas or organs are readily prepared.

Administration for the lower intestinal tract may be provided as a rectal suppository (see above) or as a suitable enema. Topical transdermal patches may also be used.

For topical administration, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan stearate, polysorbate 60, cetyl esters wax, palm oil, 2-octyldodecanol, benzyl alcohol, and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted saline, or preferably as solutions in isotonic pH adjusted sterile saline, with or without preservatives, such as benzylalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutical compositions may be formulated as ointments, such as petrolatum.

The pharmaceutical compositions of the present invention may also be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other commonly used solubilizing or dispersing agents.

The amount of protein kinase inhibitor that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that an inhibitory dose of 0.01-100mg/kg body weight/day can be administered to a patient receiving these compositions.

It will also be understood that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the particular disease undergoing therapy. The amount of inhibitor also depends on the specific compound in the composition.

Administration with another active agent

Depending on the particular protein kinase-mediated condition being treated or prevented, additional agents that are commonly administered to treat or prevent such conditions may be administered in conjunction with the compounds of the present invention.

Those additional active agents may be administered separately from the compound or composition comprising the protein kinase inhibitor, as part of a multiple dose regimen. Alternatively, those active agents may be part of a single dosage form, mixed together with the protein kinase inhibitor into a single composition.

Another aspect of the invention relates to a method of treating cancer, said method comprising administering to a subject in need thereof, sequentially or co-administered, a compound of the invention orPharmaceutically acceptable salts thereof and anticancer agents. In some embodiments, the anti-cancer agent is selected fromPlatinum medicineFor example cisplatin, oxaliplatin, carboplatin, nedaplatin or satraplatin and other derivatives;topo I inhibition Agent for treating cancerSuch as camptothecin, topotecan, irinotecan/SN 38, rubitecan and other derivatives;antimetabolitesFor example the folate families (methotrexate, pemetrexed and the like); the purine group (thioguanine, fludarabine, cladribine, 6-mercaptopurine, and the like); the pyrimidine family (cytarabine, gemcitabine, 5-fluorouracil and analogues);alkylating agentSuch as nitrogen mustards (cyclophosphamide, melphalan, chlorambucil, mechlorethamine, ifosfamide, and the like); nitrosoureas (e.g., carmustine); triazenes (dacarbazine, temozolomide); alkyl sulfonates (e.g., busulfan); procarbazine and aziridines; AntibioticFor example hydroxyurea; anthracyclines (doxorubicin, daunorubicin, epirubicin, and other derivatives); anthracenediones (mitoxantrone and the like); streptomyces (bleomycin, mitomycin C, actinomycin) and uv light.

Biological sample

The compounds and compositions of the invention are also useful as inhibitors of ATR kinase in biological samples. One aspect of the invention relates to inhibiting ATR kinase activity in a biological sample, which method comprises contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample" as used herein meansIn vitroOrIn vitroSamples include, but are not limited to, cells or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. The term "compounds as described herein" includes compounds of formula I, III, IV, IA, IIA, IIIA, IVA, IA-I, IA-ii, IA-III, V, VI and VII.

Inhibition of ATR kinase activity in a biological sample is used for a variety of purposes well known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, and biological sample storage.

Protein kinase study

Another aspect of the invention relates to the study of protein kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and comparative evaluation of novel protein kinase inhibitors. Examples of such applications include, but are not limited to, biological assays such as enzymatic assays and cell-based assays.

The activity of a compound as a protein kinase inhibitor may be determined in vitro, in vivo or in a cell line. In vitro assays include assays that measure kinase activity or inhibition of the activity of activated kinase ATPa s e. Alternative in vitro assays quantify the ability of an inhibitor to bind to a protein kinase and may be determined by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound or by performing a competition experiment in which the new inhibitor is incubated with a kinase that binds to a known radioligand. The detailed conditions for measuring the compound used as an ATR inhibitor in the present invention are shown in the following examples.

Another aspect of the invention provides methods of modulating enzymatic activity by contacting a compound described herein with ATR kinase.

Method of treatment

In one aspect, the invention provides methods for treating or lessening the severity of a disease, condition, or disorder, wherein ATR kinase is implicated in the disease state. In another aspect, the invention provides a method for treating or lessening the severity of an ATR kinase disease, condition, or disorder, wherein inhibiting enzyme activity involves treating the disease. In another aspect, the invention provides methods of treating or lessening the severity of a disease, condition or disorder using compounds that inhibit enzymatic activity by binding to ATR kinase. Another aspect provides a method for treating or lessening the severity of a kinase disease, condition or disorder by inhibiting the enzymatic activity of ATR kinase with an ATR kinase inhibitor.

One aspect of the present invention relates to a method of inhibiting ATR kinase activity in a patient comprising administering to said patient a compound described herein or a composition comprising said compound. In some embodiments, the methods are used to treat or prevent a disorder selected from proliferative and hyperproliferative diseases, such as cancer.

Another aspect of the invention provides a method of treating, preventing or lessening the severity of a proliferative or hyperproliferative disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound. In some embodiments, the subject is a patient. The term "patient" as used herein means an animal, preferably a human.

In some embodiments, the method is for treating or preventing cancer. In some embodiments, the methods are used to treat or prevent a type of cancer having a solid tumor. In another embodiment, the cancer is selected from the following cancers:mouth piece Cavity:oral cavity, lip, tongue, mouth, pharynx;heart and heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;lung (lung): bronchogenic carcinoma (squamous cell or epidermoid carcinoma, poorly differentiated small cell carcinoma, poorly differentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenocarcinoma, sarcoma, lymphoma, hamartoma, mesothelioma;gastrointestinal tract: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, pancreatic tumor), small or small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large or large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon-rectum, colorectal; a rectum part, Urogenital tract: kidney (adenocarcinoma, Wilms' tumor [ nephroblastoma ]]Lymphoma), bladder and urineTract (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);liver disease: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract;bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chondrosarcoma (osteochondral exostosis), benign chondroma, chondroblastoma, osteogenic fibroma, and giant cell tumor;nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell [ pinealoma ] ]Glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);gynaecology department: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma [ serous cystadenocarcinoma, myxocystadenocarcinoma, nontypal carcinoma)]Granulosa-thecoma, sertoli cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast;skin(s): malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, melanoma, and combinations thereof,Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; andadrenal gland : neuroblastoma.

In some embodiments, the cancer is selected from the cancers described herein. In some embodiments, the cancer is lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, or brain cancer.

In some embodiments, an "effective amount" of a compound or pharmaceutically acceptable composition is an amount effective to treat the disease. In accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective to treat or reduce the severity of the disease.

One aspect provides a method of inhibiting ATR in a patient comprising administering a compound described herein. Another embodiment provides a method of treating cancer, comprising administering to a patient a compound described herein, wherein the variables are as defined herein.

Some embodiments comprise administering to the patient an additional therapeutic agent selected from a DNA-damaging agent; wherein the additional therapeutic agent is appropriate for the disease being treated; and administering the additional therapeutic agent with the compound as a single dosage form or separately from the compound as part of a multiple dosage form.

In some embodiments, the DNA-damaging agent is selected from ionizing radiation, a mimic radioactive neocarzinostatin, a platinoid, a Topo I inhibitor, a Topo II inhibitor, an antimetabolite, an alkylating agent, an alkyl sulfonate, an antimetabolite, or an antibiotic. In other embodiments, the DNA-damaging agent is selected from ionizing radiation, a platinum-based drug, a Topo I inhibitor, a Topo II inhibitor, or an antibiotic.

Examples of platinum-based drugs include cisplatin, oxaliplatin, carboplatin, nedaplatin, satraplatin, and other derivatives. Other platinum drugs include lobaplatin and Triplatin (Triplatin). Other platinum drugs include tetranitrate (tetranitrate), picoplatin, satraplatin, ProLindac, and Aroplatin.

Examples of Topo I inhibitors include camptothecin, topotecan, irinotecan/SN 38, rubitecan, and other derivatives. Other Topo I inhibitors include Belotecan (Belotecan).

Examples of Topo II inhibitors include etoposide, daunorubicin, doxorubicin, aclarubicin, epirubicin, idarubicin, amrubicin, valrubicin, zorubicin, and teniposide.

Examples of antimetabolites include members of the folate family, members of the purine family (purine analogs), or members of the pyrimidine family (pyrimidine antagonists). Examples of the folic acid family include methotrexate, pemetrexed, and the like; examples of the purine group include thioguanine, fludarabine, cladribine, 6-mercaptopurine, and the like; examples of the pyrimidine family include cytarabine, gemcitabine, 5-fluorouracil (5FU), and the like.

Some other specific examples of antimetabolites include aminopterin, methotrexate, pemetrexed, raltitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, and hydroxyurea.

Examples of alkylating agents include nitrogen mustards, triazenes, alkyl sulfonates, procarbazine, and aziridines. Examples of nitrogen mustards include cyclophosphamide, melphalan, chlorambucil, and the like; examples of nitrosoureas include carmustine; examples of triazenes include dacarbazine and temozolomide; examples of alkyl sulfonates include busulfan.

Other specific examples of alkylating agents include nitrogen mustard, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine, lomustine, semustine, fotemustine, nimustine, ramustine, streptozocin, busulfan, mannosulfan, trooshan, carboquone, ThioTEPA, triimiquone, trittamine, procarbazine, dacarbazine, temozolomide, altretamine, dibromomannitol, actinomycin, lewisin, mitomycin, and plicamycin.

Examples of antibiotics include mitomycin, hydroxyurea; anthracyclines, anthracenediones, streptomycetaceae. Examples of anthracyclines include doxorubicin, daunorubicin, epirubicin, and other derivatives; examples of anthracenediones include mitoxantrone and the like; examples of streptomycetaceae include bleomycin, mitomycin C and actinomycin.

In some embodiments, the platinum-based drug is cisplatin or oxaliplatin; said Topo I inhibitor is camptothecin; the Topo II inhibitor is etoposide; and the antibiotic is mitomycin. In other embodiments, the platinum-based drug is selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, or satraplatin; the Topo I inhibitor is selected from camptothecin, topotecan, irinotecan/SN 38, rubitecan; the Topo II inhibitor is selected from etoposide; the antimetabolite is selected from a member of the folate, purine or pyrimidine family; the alkylating agent is selected from nitrogen mustard, nitrosourea, triazene, alkyl sulfonate, procarbazine or aziridine; and the antibiotic is selected from hydroxyurea, anthracyclines, anthracenediones or streptomycetaceae.

Another embodiment provides a method of promoting cancer cell death comprising administering to a patient a compound described herein or a composition comprising the compound.

Another embodiment provides a method of preventing DNA-damaged cell repair in a cancer cell, the method comprising administering to a patient a compound described herein or a composition comprising the compound. Another embodiment provides a method of preventing DNA damage-induced cell repair in cancer cells, the method comprising administering to a patient a compound of formula I or a composition comprising the compound.

Another embodiment provides a method of sensitizing a cell to a DNA damaging agent comprising administering to a patient a compound described herein or a composition comprising the compound.

In some embodiments, the method is used on cancer cells having defects in the ATM signaling cascade. In some embodiments, the defect is altered expression or activity of one or more of ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, or H2 AX. In another embodiment, the cell is a cancer cell that expresses a DNA-damaging oncogene. In some embodiments, the cancer cell has altered expression or activity of one or more of K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, cyclin E, cyclin A, and Rb.

Another embodiment provides the use of a compound described herein as a radiosensitizer or a chemosensitizer.

Another embodiment provides the use of a compound of formula I as a single active agent (monotherapy) for the treatment of cancer. In some embodiments, the compounds of formula I are used to treat a patient with a cancer that has a DNA-damage response (DDR) deficiency. In other embodiments, the defect is a mutation or deletion of ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, or H2 AX.

Synthetic route

The compounds disclosed herein can be prepared according to the present specification using procedures generally known to those skilled in the art. Those compounds can be analyzed by well known methods including, but not limited to, LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). The following is a general set of synthetic routes illustrating generally how the compounds of the invention may be prepared.

Scheme I-A1: preparation of compounds in which-L-R¹Is an aromatic amide

Cyclic amides disclosed in the present specification, wherein-L-R¹Is an aromatic amide: let business toReaction of the purchased ester 1 with boronic acid under Suzuki conditions gives intermediate 2. The carboxylic acid group is subjected to a coupling reaction with an amine to give the cyclic amide compound of formula I.

Scheme I-A2: preparation of compounds in which-L-R¹Is an aromatic amide

Alternatively, the compounds disclosed in the present specification, wherein-L-R, may be prepared according to procedures analogous to those described in scheme I-A2¹Is an aromatic amide, and a process analogous to that described in scheme I-A2 is a variant of the synthetic sequence described in scheme I-A1, which consists in using methyl ester 1 as starting material. The ester 1 is converted to the carboxylic acid 3, which is coupled with an amine to give the amide 4. Reacting it with boric acid under Suzuki conditions to give the compound of formula I.

Scheme I-B1: preparation of compounds wherein ring A is 1, 3, 4-oxadiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

The compounds disclosed in this specification can be prepared according to methods analogous to those described in scheme I-B1, wherein ring a is a 1, 3, 4-oxadiazole: the methyl ester 3 is reacted with boronic acid under suzuki conditions to give intermediate 8. The carboxylic acid in 8 is then coupled with a hydrazide (X ═ O) or thiohydrazide (X ═ S) to form 9. Finally, the acylhydrazide of scheme 9 is cyclodehydrated to provide the compound disclosed in this specification (formula I in scheme I-B1). Intermediate 8 is also converted to the compound of formula I in a one-pot process using reagents for both purposes (coupling and cyclodehydration).

Scheme I-B2: preparation of compounds wherein ring A is 1, 3, 4-oxadiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the compounds disclosed in this specification can be prepared according to methods analogous to those described in scheme I-B2, wherein ring A is a 1, 3, 4-oxadiazole, and synthetic schemes I-B2, which are variations of the synthetic sequences described in scheme I-B1. Coupling of hydrazide 5 with the carboxylic acid function formed intermediate 9(X ═ O). The acylhydrazide is then subjected to cyclodehydration to provide the compound of formula I as shown in scheme I-B1. When R5 is a moiety bonded to the oxadiazole ring via a C-N bond, the isothiocyanate may be used to form intermediate 9(X ═ S); followed by cyclodehydration of the thioacyl hydrazide to give the compound of formula I.

Synthetic schemes I-B3: preparation of compounds wherein ring A is 1, 3, 4-oxadiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the compounds disclosed in this specification can be prepared according to methods analogous to those described in schemes I-B3, wherein ring A is a 1, 3, 4-oxadiazole: coupling of the functional groups in 10 or 6 (acid and hydrazide respectively, both prepared by hydrolysis and hydrazinolysis of methyl ester 3 respectively) with the appropriate partner (R)₅CXNHNH₂In this case, 10 is used as raw material; r₅COOH/R₅S, in this case starting from 6), to form the acyl hydrazide intermediate 11. Then theCyclodehydration was carried out to give compound 12 in which the 1, 3, 4-oxadiazole ring had been formed. Starting point 10 or 6 is also converted to intermediate 12 in a one-pot process using reagents for both purposes (coupling and cyclodehydration). The bromo handle group (bromo handle) in oxadiazole 12 is then reacted under Suzuki conditions to give the compound of formula I. When the R group in I comprises a carboxylic acid moiety, it may be further converted (e.g., to an amide) using conditions well known in the art.

Scheme I-C1: preparation of compounds wherein ring A is 1, 2, 4-oxadiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

The compounds disclosed in this specification can be prepared according to methods analogous to those described in schemes I-C1, wherein ring a is a 1, 2, 4-oxadiazole: nitrile 2 was reacted with hydroxylamine to provide intermediate 13. The hydroxyl group in 13 is reacted with an acid chloride to give intermediate 14, which is subjected to cyclodehydration to give the compound of formula I.

Scheme I-C2: preparation of compounds wherein ring A is 1, 2, 4-oxadiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the compounds disclosed in this specification can be prepared according to methods analogous to those described in schemes I-C2, wherein ring A is a 1, 2, 4-oxadiazole: commercial nitrile 1 was reacted with hydroxylamine to afford intermediate 15. The hydroxyl group in 15 was reacted with an acid chloride to give intermediate 16, which was subjected to cyclodehydration to give intermediate 17. The bromo-treated group in 17 is then used to react with a boronic acid coupling partner under Suzuki conditions to give the compound of formula I. When the R group in I comprises a carboxylic acid moiety, it may be further converted (e.g., to an amide) using conditions well known in the art.

Scheme I-D1: preparation of compounds in which ring A is 1, 3, 4-thiadiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

The compounds disclosed in this specification can be prepared according to procedures analogous to those described in schemes I-D1, wherein ring a is 1, 3, 4-thiadiazole: the methyl ester 3 is reacted with boronic acid under suzuki conditions to give intermediate 8. The carboxylic acid of 8 is then subjected to a coupling reaction with thiohydrazide to form 18. Finally, the thioacyl hydrazide in 18 is subjected to cyclodehydration to give the compound of formula I. The intermediate 8 can be converted to the compound of formula I in a one-pot process using reagents for both purposes (coupling and cyclodehydration).

Scheme I-D2: preparation of compounds in which ring A is 1, 3, 4-thiadiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the compounds disclosed in this specification can be prepared according to procedures analogous to those described in schemes I-D2, wherein ring A is 1, 3, 4-thiadiazole: reacting the acidic functional group of 10 with a suitable partner (R)₅CSNHNH₂) Coupling to form intermediate 19. Then carrying out cyclodehydration to obtainCompound 20, wherein the 1, 3, 4-thiadiazole ring has been completed. Starting point 10 can be converted to 20 in a one-pot process using reagents for both purposes (coupling and cyclodehydration). The bromine treated group in thiadiazole 20 is then reacted with boronic acid under suzuki conditions to yield the compound of formula I. When the R group in I comprises a carboxylic acid moiety, it may be further converted (e.g., to an amide) using conditions well known in the art.

Scheme I-E1: preparation of compounds wherein ring A is isoxazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

The compounds disclosed in this specification can be prepared according to procedures analogous to those described in schemes I-E1, wherein ring a is isoxazole: commercially available 2-amino-3, 5-dibromopyrazine 21 was Sonogashira coupled with TMS-acetylene to give intermediate 22, fully protecting the amino group as a di-Boc species 23. And carrying out Suzuki coupling with other bromine treatment groups, and simultaneously carrying out TMS deprotection to obtain an intermediate 24. The alkyne 24 is finally reacted with N-hydroxy aroyl chloride in a cyclocondensation to give the compound of formula I.

Scheme I-E2: preparation of compounds wherein ring A is isoxazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the compounds disclosed in this specification can be prepared according to methods analogous to those described in schemes I-E2, wherein ring a is isoxazole: the TMS-protected intermediate 23 described in schemes I-E1 may be deprotected to provide the alkyne compound 25. Alkyne 25 is reacted with N-hydroxyaroyl chloride in a cyclocondensation to give intermediate 26, in which the isoxazole ring has been built up. The bromine treated group in isoxazole 26 is then reacted with boronic acid under Suzuki conditions to give compound 27. Finally deprotection of the N-protecting group in 27 affords compounds of formula I. When the R group in I comprises a carboxylic acid moiety, it may be further converted (e.g., to an amide) using conditions well known in the art.

Scheme I-F1: preparation of compounds in which ring A is 1, 2, 4-triazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the compounds disclosed in this specification can be prepared according to analogous methods to those described in schemes I-F1, starting from methyl ester 3, wherein ring A is 1, 2, 4-triazole. Ester 3 was reacted with boronic acid under Suzuki conditions to give intermediate 4. When the R group comprises a carboxylic acid moiety, it may be further converted (e.g., to an amide) using conditions well known in the art. The methyl ester group in 4 is then converted to the hydrazide by reaction with hydrazine to give 5. Finally, coupling of the hydrazide group in 5 with hydrazine followed by cyclodehydration gives the compounds of formula I.

Scheme I-F2: preparation of compounds in which ring A is 1, 2, 4-triazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, it can be according to a similar method as described in scheme I-F2A compound disclosed in the present specification, wherein ring a is 1, 2, 4-triazole: reacting the R function in 1 or 3 (nitrile and methyl ester, respectively) with a suitable coupling partner (R)₅CONHNH₂In this case, 1 is taken as a raw material; r₅CN, provided 6) is used (after conversion of the appropriate 3 to hydrazide 6). Cyclodehydration was then carried out to give intermediate 7, in which the 1, 2, 4-triazole ring had been constituted. The bromo-treated group in triazole 7 is then reacted with boronic acid under Suzuki conditions to give the compound of formula I. When the R group comprises a carboxylic acid moiety, it may be further converted (e.g., to an amide) using conditions well known in the art.

Scheme I-G1: preparation of compounds in which ring A is benzoxazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Benzoxazole compounds of formula VI can be prepared according to procedures analogous to those described in schemes I-G1: commercial nitrile 1 is reacted with aminophenol to give benzoxazole which is then reacted with boronic acid under suzuki conditions to give the compound of formula VI.

Scheme I-H1: preparation of compounds in which ring A is benzothiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

The benzothiazole compounds of formula VI may be prepared according to procedures analogous to those described in schemes I-H1: commercial nitrile 1 is reacted with aminothiophenol (benzanethiol) under Suzuki conditions to give benzothiazole, which is then reacted with boric acid under Suzuki conditions to give the compound of formula VI.

Scheme I-H2: preparation of compounds of which benzothiazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the benzothiazole compounds of formula VI may be prepared according to procedures analogous to those described in schemes I-H2: reaction of methyl ester 3 with boronic acid under Suzuki conditions gives intermediate 8. Cyclization of intermediate 8 with an aminothiophenol affords compounds of formula VI.

Scheme I-I1: preparation of compounds in which ring A is imidazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

The benzimidazole compounds of formula I may be prepared according to methods analogous to those described in schemes I-I1: reaction of methyl ester 3 with boronic acid under Suzuki conditions gives intermediate 8. Cyclization of intermediate 8 with benzene 1, 2-diamine affords compounds of formula I.

Scheme I-I2: preparation of compounds in which ring A is imidazole

Wherein R is- (L-NR)¹R²)_pOr- (J)₂)_q

Alternatively, the benzimidazole compounds of formula I may be prepared according to methods analogous to those described in schemes I-I2: the acidic functionality of 3 is reacted with benzene 1, 2-diamine to give the benzimidazole intermediate 9. Intermediate 9 is then reacted with boronic acid under Suzuki conditions to give the compound of formula I.

Examples

It is to be understood that the specific conditions shown below are examples only and are not meant to limit the scope of conditions for preparing, analyzing or testing the compounds of the present invention. The present invention also encompasses conditions known to those skilled in the art for preparing, analyzing and testing the compounds of the present invention.

HPLC method

The term "rt (min)" as used herein means the HPLC retention time in minutes associated with a compound. Unless otherwise indicated, the HPLC method used to obtain the reported retention times was as follows:

column: ACE C8 column, 4.6X 150mm

Gradient: 0-100% acetonitrile + methanol 60: 40(20mM Tris phosphate)

Flow rate: 1.5 mL/min

And (3) detection: 225 nm.

HNMR method

Recording at 400MHz using a Bruker DPX 400 instrument¹H-NMR spectrum.

Mass spectrometry

Mass spectral samples were analyzed on a MicroMass Quattro Micro mass spectrometer operating in single MS mode with electrospray ionization. The sample is introduced into the mass spectrometer using chromatography. The mobile phase for all mass analyses consisted of 10mM ammonium acetate pH 7 and a 1: 1 acetonitrile-methanol mixture, column gradient conditions 5% -100% acetonitrile-methanol, gradient time within 3.5min and 5min run time on an ACE C83.0x75mm column. The flow rate was 1.2 ml/min.

The following compounds were prepared and analyzed as follows.

Example 1: 3-amino-6- (4-methoxyphenyl) -N-phenylpyrazine-2-carboxamide (Compound I-1)

Synthesis scheme A

Method A

Step 1: 3-amino-6-bromopyrazine-2-carboxylic acid methyl ester

A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35g, 54.53mmol) and N-bromo-succinimide (9.705g, 54.53mmol) was stirred in MeCN (100mL) at room temperature overnight. Filtration gave a precipitate, which was washed with MeCN and dried to give the desired product as a yellow solid (11.68g, 92% yield)

1H NMR (400.0MHz, DMSO)3.85(s, 3H), 7.55(br s, 2H) and 8.42(s, 1H) ppm; MS (ES)⁺)233

Step 2: 3-amino-6-bromopyrazine-2-carboxylic acid

A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid methyl ester (5.11g, 22.02mmol) and lithium hydroxide (2.637g, 110.1mmol) in MeOH (20mL) and H2O (20mL) was heated to 90 ℃ for 2 hours. The reaction mixture was cooled, neutralized with HCl and the resulting precipitate was collected by filtration. It was used in the next step without further purification (4.80g, 99% yield).

And step 3: 3-amino-6-bromo-N-phenylpyrazine-2-carboxamides

A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (3.5g, 16.05mmol), 1, 1' -carbonyldiimidazole (5.205g, 32.10mmol), DIPEA (2.282g, 3.075mL, 17.66mmol) and DMAP (98.04mg, 0.8025mmol) was combined in DMSO (131.2mL) and stirred for 30 min. Aniline (1.495g, 1.463mL, 16.05mmol) was then added and the resulting solution was stirred at RT for 18 hours. Water was then added and the product was collected by filtration to give a brown powder (3.5g, 74% yield).

1H NMR(400.0MHz，DMSO)d 7.04(1H，m)，7.29(2H，m)，7.72(4H，m)，8.36(1H，s)，10.22(NH₂)ppm；MS(ES⁺)295。

And 4, step 4: 3-amino-6- (4-methoxyphenyl) -N-phenylpyrazine-2-carboxamide (Compound I-1)

Greenhouse tube was charged with 4-methoxyphenylboronic acid (31.4mg, 0.207mmol), a solution of dichloropalladium, triphenylphosphine (4.84mg, 0.0069mmol) and 3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (40.45mg, 0.138mmol) in DMF (0.81mL), followed by Na₂CO₃(2M solution, 207uL, 0.414 mmol). The mixture was purged with nitrogen and heated to 88 ℃ for 18 hours. Then, the user can use the device to perform the operation,

the reaction was filtered to remove inorganic materials and the residue obtained was purified by reverse phase preparative HPLCSubstance [ WatersSunfire C18, 10uM, 100A column, gradient 10% -95% B (solvent A: 0.05% TFA in water, solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were lyophilized to give the title compound as a solid (18.56mg, 38% yield). MS (ES)⁺)321

Compounds I-1 to I-41 were prepared using method A.

Compound I-23-amino-6- (3-cyanopyridin-4-yl) -N-phenylpyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO) d 7.17(t, J ═ 7.3Hz, 1H), 7.39-7.43(m, 2H), 7.81-7.83(m, 2H), 8.30(d, J ═ 5.4Hz, 2H), 8.40(s, 1H), 8.91(d, J ═ 5.5Hz, 1H), 9.13(s, 1H), 9.17(s, 1H) and 10.16(s, 1H) ppm; MS (ES) ⁺)317

The compound I-33-amino-N-phenyl-6- (4- (2- (piperidin-1-yl) ethylcarbamoyl) phenyl) pyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO) d 3.35(s, 3H), 7.17(t, J ═ 7.4Hz, 1H), 7.43-7.39(m, 2H), 7.78(t, J ═ 7.8Hz, 2H), 7.82(d, J ═ 7.7Hz, 2H), 7.92-7.94(m, 1H), 8.60-8.66(m, 2H), 9.05(s, 1H) and 10.50(s, 1H) ppm; MS (ES)⁺)369

Compound I-43-amino-6- (4-fluorophenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400.0MHz，DMSO)d 7.16(t，J＝7.3Hz，1H)，7.32(t，J＝8.9Hz，2H)，7.38-7.42(m，2H)，7.69(s，2H)，7.81-7.83(m，2H)，8.28-8.31(m，2H)，8.92(s，1H)，10.42(s，1H)ppm；MS(ES⁺)309

Compound I-53-amino-6- (4- (methylsulfonylamino) phenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400.0MHz，DMSO)d 7.16(t，J＝7.4Hz，1H)，7.33(d，J＝8.7Hz，2H)，7.38-7.42(m，2H)，7.65(s，2H)，7.83(d，J＝7.6Hz，2H)，8.21(d，J＝8.7Hz，2H)，8.90(s，1H)，9.92(s，1H)，10.37(s，1H)ppm；MS(ES⁺)384

Compound I-63-amino-N-phenyl-6- (2- (trifluoromethyl) phenyl) pyrazine-2-carboxamide 1H NMR (400.0MHz, DMSO) d 7.11-7.16(m, 1H), 7.36-7.40(m, 2H), 7.69-7.72(m, 3H), 7.80-7.84(m, 4H), 7.93(d, J ═ 7.8Hz, 1H), 8.52(s, 1H), 10.12(s, 1H) ppm; MS (ES)⁺)359

Compound I-74- (5-amino-6- (phenylcarbamoyl) pyrazin-2-yl) benzoic acid

1H NMR(400MHz，DMSO)7.17(1H，t)，7.41(2H，t)，7.83(4H，d)，8.03(2H，d)，8.37(2H，d)，9.01(1H，s)，10.45(1H，s)，13.03(1H，br s)ppm；MS(ES⁺)335

Compound I-83- (5-amino-6- (phenylcarbamoyl) pyrazin-2-yl) benzoic acid

1H NMR(400MHz，DMSO)7.16(1H，t)，7.38-7.42(3H，m)，7.64(2H，br s)，7.81(2H，d)，7.88(1H，d)，8.17(1H，d)，8.46(1H，d)，8.85(1H，s)，10.39(1H，s)ppm；MS(ES⁺)335

Compound I-93-amino-6- (3-fluorophenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400.0MHz，DMSO)d 7.15-7.25(m，2H)，7.40(dd，J＝1.7，15.9Hz，1H)，7.41(s，1H)，7.52(t d，J＝8.0，4.7Hz，1H)，7.80-7.82(m，4H)，8.06(d，J＝8.0Hz，8.17-8.20(m，1H)，8.97(s，1H)，10.46(s，1H)ppm；MS(ES⁺)309

Compound I-103-amino-6- (3-cyanophenyl) -N-phenylpyrazine-2-carboxamide

MS(ES⁺)316

Compound I-113-amino-N-phenyl-6-o-tolylpyrazine-2-carboxamide

MS(ES⁺)305

Compound I-123-amino-6- (3-morpholinophenyl) -N-phenylpyrazine-2-carboxamide;

MS(ES+)376

compound I-133-amino-6- (4-morpholinophenyl) -N-phenylpyrazine-2-carboxamide

MS(ES+)376

Compound I-143-amino-6- (2-fluorophenyl) -N-phenylpyrazine-2-carboxamide

MS(ES⁺)309

Compound I-153-amino-N, 6-diphenylpyrazine-2-carboxamide; MS (ES)⁺)291

Compound I-163-amino-6- (4- (hydroxymethyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)321

Compound I-176- (4-acetylphenyl) -3-amino-N-phenylpyrazine-2-carboxamide

MS(ES⁺)333

Compound I-183-amino-6- (3-carbamoylphenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)334

Compound I-193-amino-6- (2- (hydroxymethyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)321

Compound I-203-amino-6- (3- (morpholine-4-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)404

Compound I-213-amino-6- (4-cyanophenyl) -N-phenylpyrazine-2-carboxamide

MS(ES⁺)316

Compound I-226- (3-acetylphenyl) -3-amino-N-phenylpyrazine-2-carboxamide

MS(ES⁺)333

Compound I-233-amino-6- (4- (2- (4-hydroxypiperidin-1-yl) acetyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)432

Compound I-243-amino-6- (4- (dimethylcarbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)362

Compound I-253-amino-6- (3- (methylsulfonylamino) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)384

Compound I-263-amino-6- (3- (morpholine-4-carbonyl) phenyl) -N- (4- (pyrrolidin-1-yl) phenyl) pyrazine-2-carboxamide; MS (ES +)473

Compound I-273-amino-6- (3-carbamoylphenyl) -N- (2-methoxyphenyl) pyrazine-2-carboxamide; MS (ES +)364

Compound I-283-amino-6- (4- (dimethylcarbamoyl) phenyl) -N- (2-methoxyphenyl) pyrazine-2-carboxamide; MS (ES +)392

The compounds I-293-amino-6- (1H-indol-5-yl) -N- (2-methoxyphenyl) pyrazine-2-carboxamide 1H NMR (400.0MHz, DMSO) d 4.03(s, 3H), 6.55(d, J ═ 1.9Hz, 1H), 7.03-7.05(m, 1H), 7.13-7.19(m, 2H), 7.43(t, J ═ 2.7Hz, 1H), 7.55(d, J ═ 8.6Hz, 2H), 7.87(dd, J ═ 1.6, 8.6Hz, 1H), 8.31(s, 1H), 8.39(dd, J ═ 1.4, 7.9Hz, 1H), 8.99(s, 1H), 10.85(s, 1H) and 11.27(s, 1H) ppm; MS (ES)⁺)360

Compound I-303-amino-6- (furan-2-yl) -N- (2-methoxyphenyl) pyrazine-2-carboxamide 1H NMR (400.0MHz, DMSO) d 3.98(s, 3H), 6.56(s, 1H), 6.69(s, 1H), 7.00-7.03(m, 2H), 7.15(s, 1H), 7.86(br s, 2H), 7.86(s, 1H), 8.32(d, 1H), 8.72(s, 1H) and 10.51(s, 1H) ppm; MS (ES) ⁺)311

Compound I-313-amino-N-phenyl-6- (1H-pyrazol-5-yl) pyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO) d 6.98(d, J ═ 10.5Hz, 1H), 7.18(t, J ═ 7.4Hz, 1H), 7.40-7.44(m, 2H), 7.67(s, 3H), 7.81(d, J ═ 7.7Hz, 2H), 8.83(s, 1H), 10.54(s, 1H) and 13.80(s, 1H) ppm; MS (ES)⁺)281

Compound I-323-amino-6- (6-hydroxypyridin-3-yl) -N-phenylpyrazine-2-carboxamide 1H NMR (400.0MHz, DMSO) d 6.45(d, J ═ 9.6Hz, 1H), 7.14-7.18(m, 1H),7.38-7.42(m, 2H), 7.58(s, 2H), 7.78-7.80(m, 2H), 8.31(d, J ═ 2.5Hz, 1H), 8.39(dd, J ═ 2.6, 9.6Hz, 1H), 8.79(s, 1H), 10.42(s, 1H) and 12.00(s, 1H) ppm; MS (ES)⁺)308

Compound I-333-amino-N-phenyl-6- (pyridin-4-yl) pyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO) d 7.18(t, J ═ 7.5Hz, 1H), 7.41(dd, J ═ 1.8, 14.1Hz, 2H), 7.82(dd, J ═ 0.8, 8.4Hz, 2H), 7.90(s, 2H), 8.25(dd, J ═ 1.6, 4.6Hz, 2H), 8.67(dd, J ═ 1.4, 4.8Hz, 2H), 9.07(s, 1H) and 10.48(s, 1H) ppm; MS (ES)⁺)292

Compound I-343-amino-6- (6-morpholinopyridin-3-yl) -N-phenylpyrazine-2-carboxamide; MS (ES +)377

Compound I-353-amino-N- (2-methoxyphenyl) -6- (thiophen-2-yl) pyrazine-2-carboxamide; MS (ES +)327

Compound I-363-amino-6- (1H-indazol-5-yl) -N- (2-methoxyphenyl) pyrazine-2-carboxamide; MS (ES +)361

Compound I-373-amino-6- (furan-3-yl) -N- (2-methoxyphenyl) pyrazine-2-carboxamide; MS (ES +)311

Compound I-383-amino-6- (2-methoxypyridin-4-yl) -N-phenylpyrazine-2-carboxamide; MS (ES +)322

Compound I-393-amino-6- (1H-indazol-5-yl) -N-phenylpyrazine-2-carboxamide

MS(ES⁺)331

Compound I-403-amino-N-phenyl-6- (pyrimidin-5-yl) pyrazine-2-carboxamide

MS(ES⁺)293

Compound I-413-amino-6- (furan-2-yl) -N-phenylpyrazine-2-carboxamide

MS(ES⁺)281

Example 2: (R) -3-amino-N-phenyl-6- (4- (2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carbonyl) phenyl) pyrazine-2-carboxamide (Compound I-42)

Synthesis scheme B

Compound I-42 was prepared by using method a, steps 1-3, then using method I-B, steps 1-2.

Method I-B

Step 1: 3- (5-amino-6- (phenylcarbamoyl) pyrazin-2-yl) benzoic acid

3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (2.5g, 8.529mmol), 3-dihydroxyborobenzoic acid (1.415g, 8.527mmol) and Na₂CO₃A mixture of (1.808g, 17.06mmol) was suspended in MeCN (40 mL)/water (40 mL). Degassing the mixture (5x N)₂Vacuum cycle), add Pd (PPh)₃)₄(985.6mg, 0.8529 mmol). The mixture was degassed and heated to 90 ℃. After 2 hours, the mixture was cooled and concentrated to half the original volume. The resulting yellow precipitate was collected and washed with DCM and water (3.05g, 86% yield). 1H NMR (400MHz, DMSO) d 7.16(1H, t), 7.38-7.42(3H, m), 7.64(2H, br s), 7.81(2H, d), 7.88(1H, d), 8.17(1H, d), 8.46(1H, d), 8.85(1H, s), 10.39(1H, s) ppm; MS (ES) ⁺)335

Step 2: (R) -3-amino-N-phenyl-6- (4- (2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carbonyl) phenyl) pyrazine-2-carboxamide

1- [ [ (2R) -pyrrolidin-2-yl group]Methyl radical]Pyrrolidine (69.23mg, 0.449mmol) was weighed into Greenhouse tubes and treated with a solution of 3- (5-amino-6- (phenylcarbamoyl) pyrazin-2-yl) benzoic acid (50mg, 0.150mmol), CDI (48.51mg, 0.299mmol) and DMAP (1.82mg, 0.015mmol) in DMSO (1mL stock solution). DIPEA (78.2uL, 0.449mmol) was then added and the mixture was stirred at 38 ℃ for 6 hours. The reaction mixture was filtered and the resulting residue was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10uM, 100A column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA, solvent B: CH 3CN) over 16 min, 25mL/min]. The fractions were lyophilized to give the title compound as a solid (51.87mg, 73% yield). (ES)⁺)471

Compounds I-42 to I-81 were prepared using method A, step 1-3, followed by method I-B, step 1-2.

Compound I-436- (4- (1, 4-diazepan-1-carbonyl) phenyl) -3-amino-N-phenylpyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO)1.44-1.47(m, 1H), 1.53-1.58(m, 1H), 2.57-2.61(m, 1H), 2.62-2.69(m, 2H), 2.74-2.80(m, 1H), 3.15-3.20(m, 2H), 3.40-3.46(m, 2H), 6.91-6.96(m, 1H), 7.15-7.19(m, 2H), 7.23-7.28(m, 2H), 7.51(br s, 2H), 7.58-7.60(m, 2H), 8.05-8.08(m, 2H), 8.74(s, 1H) and 10.20(s, 1H) ppm; MS (ES) ⁺)417

Compound I-443-amino-6- (4- (3-methoxyazetidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400MHz，DMSO)3.22(3H，s)，3.87(1H，br dd)，4.18(1H，br d)，4.23-4.29(2H，br dd)，4.47-4.49(1H，m)，7.17(1H，t)，7.40(2H，t)，7.75(2H，d)，7.79(2H，br s)，7.83(2H，d)，8.29(2H，d)，9.00(1H，s)，10.44(1H，s)ppm；MS(ES⁺)404

Compound I-453-amino-6- (4- ((2-methoxyethyl) (methyl) carbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400MHz，DMSO)3.00(3H，br s)，3.45(3H，br s)，3.61(2H，br d)，7.17(1H，t)，7.41(2H，t)，7.49(2H，d)，7.76(2H，br s)，7.84(2H，d)，8.29(1H，d)，8.97(1H，s)，10.44(1H，s)ppm；MS(ES⁺)406

The compound I-463-amino-N-phenyl-6- (4- (2- (pyrrolidin-1-yl) ethylcarbamoyl) phenyl) pyrazine-2-carboxamide

1H NMR(400MHz，DMSO)1.80(4H，br s)，3.51(2H，br s)，7.18(1H，t)，7.41(2H，t)，7.81-7.85(4H，m)，7.95(2H，d)，8.35(2H，d)，8.65(1H，br s)，9.02(1H，s)，10.44(1H，s)ppm；MS(ES⁺)431

The compound I-473-amino-N-phenyl-6- (4- (tetrahydro-2H-pyran-4-ylcarbamoyl) phenyl) pyrazine-2-carboxamide

1H NMR(400MHz，DMSO)1.56-1.67(2H，m)，1.75-1.80(2H，m)，3.29-3.44(2H，m)，3.88-3.92(2H，m)，4.00-4.07(1H，m)，7.15(1H，t)，7.41(2H，t)，7.79(2H，br s)，7.82(2H，d)，7.97(2H，d)，8.33(2H，d)，8.40(1H，d)，9.01(1H，s)，10.44(1H，s)ppm；MS(ES⁺)418

Compound I-483-amino-6- (3- (1-methylpiperidin-4-ylcarbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400MHz，DMSO)1.55-1.64(2H，m)，1.76-1.81(2H，m)，1.93(2H，t)，2.16(3H，s)，2.75(2H，br d)，3.72-3.76(1H，m)，7.12(1H，t)，7.36(2H，t)，7.54(1H，t)，7.72(2H，br s)，7.78-7.83(3H，m)，8.37(2H，dd)，8.55(1H，s)，8.98(1H，s)，10.44(1H，s)ppm；MS(ES⁺)431

Compound I-493-amino-N-phenyl-6- (4- (2- (piperidin-1-yl) ethylcarbamoyl) phenyl) pyrazine-2-carboxamide

1H NMR(400MHz，DMSO)1.30-1.40(2H，m)，1.46-1.53(4H，m)，2.33(4H，m)，2.45(2H，t)，3.37-3.44(2H，m)，7.16(1H，t)，7.41(2H，t)，7.79(2H，br s)，7.81(2H，d)，7.95(2H.d)，8.34(2H，d)，8.48(1H，t)，9.00(1H，s)，10.45(1H，s)ppm；MS(ES⁺)445

Compound I-503-amino-6- (3- (4- (hydroxymethyl) piperidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400MHz，DMSO)1.10-1.22(3H，m)，1.65(2H，br s)，1.79(1H，br d)，2.77(1H，br t)，3.05(1H，br t)，3.27(2H，d)，3.64(1H，br d)，4.52(1H，br s)，7.17(1H，t)，7.38-7.42(3H，m)，7.55(1H，t)，7.73(2H，br s)，7.80(2H，d)，8.19(1H，s)，8.29(1H，d)，8.96(1H，s)，10.45(1H，s)ppm；MS(ES⁺)432

Compound I-513-amino-6- (4- (cyclopropylcarbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400MHz，DMSO)0.59-0.67(2H，m)，0.69-0.74(2H，m)，2.84-2.91(1H，m)，7.17(1H，t)，7.21(2H，t)，7.79(2H，br s)，7.81(2H，d)，7.95(2H，d)，8.39(2H，d)，8.53(1H，d)，8.971H，s)，10.46(1H，s)ppm；MS(ES⁺)374

Compound I-523-amino-6- (3- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)419

The compound I-533-amino-N-phenyl-6- (3- (piperazine-1-carbonyl) phenyl) pyrazine-2-carboxamide; MS (ES +)403

Compound I-543-amino-N-phenyl-6- (3- (2- (pyrrolidin-1-yl) ethylcarbamoyl) phenyl) pyrazine-2-carboxamide; MS (ES +)431

Compound I-553-amino-6- (3- (3- (dimethylamino) pyrrolidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)431

Compound I-563-amino-N-phenyl-6- (3- (4- (pyrrolidin-1-yl) piperidine-1-carbonyl) phenyl) pyrazine-2-carboxamide; MS (ES +)471

Compound I-573-amino-6- (3- (4-hydroxycyclohexylcarbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)432

Compound I-583-amino-6- (3- (4- (2-cyanoethyl) piperazine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)456

Compound I-593-amino-6- (3- (4-methylpiperazine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)417

Compound I-603-amino-6- (3- (3-methoxyazetidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)404

Compound I-613-amino-N-phenyl-6- (3- (2- (piperidin-1-yl) ethylcarbamoyl) phenyl) pyrazine-2-carboxamide; MS (ES +)445

Compound I-623-amino-6- (3- (4-carbamoylpiperidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)445

Compound I-633-amino-N-phenyl-6- (3- (pyrrolidine-1-carbonyl) phenyl) pyrazine-2-carboxamide; MS (ES +)388

Compound I-643-amino-6- (4- (1-methylpiperidin-4-ylcarbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)431

Compound I-653-amino-6- (3- (3-hydroxypyrrolidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)404

Compound I-663-amino-N-phenyl-6- (3- (tetrahydro-2H-pyran-4-ylcarbamoyl) phenyl) pyrazine-2-carboxamide; MS (ES +)418

Compound I-673-amino-6- (3- ((2-methoxyethyl) (methyl) carbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)406

Compound I-683-amino-6- (4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)419

Compound I-693-amino-N-phenyl-6- (4- ((tetrahydro-2H-pyran-4-yl) methylcarbamoyl) phenyl) pyrazine-2-carboxamide; MS (ES +)432

Compound I-703-amino-N-phenyl-6- (4- (pyrrolidine-1-carbonyl) phenyl) pyrazine-2-carboxamide; MS (ES +)388

Compound I-713-amino-N-phenyl-6- (4- (4- (pyrrolidin-1-yl) piperidine-1-carbonyl) phenyl) pyrazine-2-carboxamide; MS (ES +)471

Compound I-723-amino-6- (4- (azetidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)374

The compound I-733-amino-6- (4- (4-methylpiperazine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)417

The compound I-743-amino-N-phenyl-6- (4- (piperazine-1-carbonyl) phenyl) pyrazine-2-carboxamide; MS (ES +)403

The compound I-753-amino-6- (4- (3-hydroxypyrrolidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)404

Compound I-763-amino-6- (4- (3- (dimethylamino) pyrrolidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)431

Compound I-773-amino-6- (4- (4-carbamoylpiperidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)445

Compound I-783-amino-N-phenyl-6- (4- (piperidine-1-carbonyl) phenyl) pyrazine-2-carboxamide; MS (ES +)402

Compound I-793-amino-6- (4- (4- (hydroxymethyl) piperidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)432

Compound I-803-amino-6- (4- (4- (dimethylamino) piperidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)445

Compound I-813-amino-6- (4- (4- (2-cyanoethyl) piperazine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; MS (ES +)456

Example 3: 3-amino-6- (4- (methylsulfonyl) phenyl) -N-phenylpyrazine-2-carboxamide (Compound I-82)

Synthesis scheme C

Preparation of Compound I-82 Using method A, step 1, followed by method I-C, steps 1-3

Method I-C

Step 1: 3-amino-6- (4- (methylsulfonyl) phenyl) pyrazine-2-carboxylic acid methyl ester

Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (1.5g, 6.465mmol), (4-methylsulfonylphenyl) boronic acid (1.552g, 7.758mmol), bis (triphenylphosphine) palladium (II) dichloride (226.9mg, 0.3233mmol) and Na ₂CO₃A mixture of (9.700mL, 2M, 19.40mmol) in DME (18.75mL) was heated in a microwave at 110 ℃ for 1 hour. The resulting mixture was diluted with EtOAc and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give the title compound (600mg, 53% yield).

1H NMR(400MHz，DMSO)3.25(3H，s)，3.92(3H，s)，7.61(2H，br s)，8.00(2H，m)，8.26(2H，m)，9.03(H，s)ppm；MS(ES⁺)308

Step 2: 3-amino-6- (4- (methylsulfonyl) phenyl) pyrazine-2-carboxylic acid

A mixture of methyl 3-amino-6- (4- (methylsulfonyl) phenyl) pyrazine-2-carboxylate (3.50g, 11.39mmol) and LiOH (1.364g, 56.95mmol) was dissolved in methanol (14mL) and water (14mL) and heated at 90 ℃ for 2 hours. The reaction mixture was cooled and neutralized with 1M HCl. The resulting precipitate was collected by filtration to give the pure product as a yellow solid (3.32g, 99% yield). MS (ES)⁺)293

And step 3: 3-amino-6- (4- (methylsulfonyl) phenyl) -N-phenylpyrazine-2-carboxamide (Compound I-82)

A mixture of 3-amino-6- (4-methylsulfonylphenyl) pyrazine-2-carboxylic acid (1.5g, 5.114mmol), diethoxyphosphoryl carbonitrile (926.8mg, 849.5. mu.L, 5.114mmol), aniline (476.2mg, 465.9. mu.L, 5.114mmol) and triethylamine (1.035g, 1.426mL, 10.23mmol) was stirred in DME (18.75mL) at 120 ℃ for 18 h. Water was then added and the resulting solid was collected by filtration. The solid was triturated with acetone and dried to give the desired product (1.335g, 71% yield). 1H NMR (400.0MHz, DMSO) d3.28(s, 3H), 7.18(t, J ═ 7.3Hz, 1H), 7.41(t, J ═ 7.8Hz, 2H), 7.82(d, J ═ 7.9Hz, 2H), 7.89(s, 2H), 8.01(d, J ═ 8.4Hz, 2H), 8.51(d, J ═ 8.4Hz, 2H), 9.04(s, 1H) and10.47(s, 1H) ppm; MS (ES) ⁺)369

All compounds I-82 to I-108 were prepared using method a, step 1, then using method I-C, steps 1-3.

Compound I-823-amino-6- (4- (methylsulfonyl) phenyl) -N-phenylpyrazine-2-carboxamide

1H NMR(400.0MHz，DMSO)d 3.28(s，3H)，7.18(t，J＝7.4Hz, 1H), 7.43-7.39(m, 2H), 7.83-7.81(m, 2H), 7.89(s, 2H), 8.01(dd, J ═ 1.6, 7.0Hz, 2H), 8.51(d, J ═ 8.5Hz, 2H), 9.04(s, 1H) and 10.46(s, 1H) ppm; MS (ES)⁺)369.

Compound I-833-amino-N- (1H-indol-7-yl) -6- (pyridin-3-yl) pyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO) d 6.50(dd, J ═ 2.0, 2.9Hz, 1H), 7.04(t, J ═ 7.7Hz, 1H), 7.21(d, J ═ 7.4Hz, 1H), 7.35(t, J ═ 2.8Hz, 1H), 7.50(d, J ═ 7.8Hz, 1H), 7.79(dd, J ═ 5.2, 8.0Hz, 3H), 8.73(dd, J ═ 1.2, 5.2Hz, 1H), 9.03(d, J ═ 8.2Hz, 1H), 9.09(s, 1H), 9.65(d, J ═ 1.9Hz, 1H), 10.67(s, 1H) and 11.00(s, 1H); MS (ES)⁺)331

Compound I-843-amino-N- (4-methoxyphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO) d 3.76(s, 3H), 6.98(dd, J ═ 2.1, 6.9Hz, 2H), 7.69(dd, J ═ 2.1, 6.9Hz, 2H), 7.84(dd, J ═ 5.2, 8.1Hz, 3H), 8.76(dd, J ═ 1.2, 5.2Hz, 1H), 9.01-9.06(m, 2H), 9.62(d, J ═ 1.9Hz, 1H) and 10.46(s, 1H) ppm; MS (ES) ⁺)322

Compound I-853-amino-N-phenyl-6- (pyridin-3-yl) pyrazine-2-carboxamide

1H NMR (400.0MHz, DMSO) d 7.17(t, 1H), 7.49(t, 2H), 7.68(t, 1H), 7.82(d, 2H), 7.87(br s, 2H), 8.68(d, 1H), 8.81(d, 1H), 9.12(s, 1H), 9.51(s, 1H) and 10.48(s, 1H) ppm; MS (ES)⁺)292

Compound I-863-amino-N- (3-methoxyphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide

1H NMR (400MHz, DMSO) d 3.79(3H, s), 6.74(1H, dd), 7.30(1H, t), 7.44(1H, d), 7.50-7.52(2H, m), 7.8(2H, br s), 8.59-8.62(2H, m), 9.00(1H, s), 9.44(1H, s) and 10.42(1H, s) ppm; MS (ES)⁺)322

Compound I-873-amino-N- (3-cyanophenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)317

Compound I-883-amino-N- (3-carbamoylphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)335

Compound I-893-amino-6- (pyridin-3-yl) -N- (pyrimidin-4-yl) pyrazine-2-carboxamide; MS (ES +)294

Compound I-903-amino-N- (3- (dimethylamino) phenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)335

Compound I-913-amino-6- (pyridin-3-yl) -N-o-tolylpyrazine-2-carboxamide; MS (ES)⁺)306

Compound I-923-amino-N- (4-carbamoylphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)335

Compound I-933-amino-N- (4-acetamidophenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)349

Compound I-943-amino-N- (4-fluorophenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)310

Compound I-953-amino-N- (3-acetamidophenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)349

Compound I-963-amino-N- (2-fluorophenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)310

Compound I-973-amino-N- (pyridin-2-yl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)293

Compound I-983-amino-6- (pyridin-3-yl) -N- (pyridin-4-yl) pyrazine-2-carboxamide; MS (ES +)293

The compound I-993-amino-N- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-4-yl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)372

Compound I-1003-amino-N- (5-acetylamino-2-methoxyphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)379

Compound I-1013-amino-6- (pyridin-3-yl) -N- (3-sulfamoylphenyl) pyrazine-2-carboxamide; MS (ES +)371

Compound I-1023-amino-6- (pyridin-3-yl) -N- (2- (trifluoromethoxy) phenyl) pyrazine-2-carboxamide; MS (ES +)376

Compound I-1033-amino-N- (3-fluorophenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)310

Compound I-1043-amino-N- (1H-indol-5-yl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)331

Compound I-1053-amino-N- (1H-indol-6-yl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)331

Compound I-1063-amino-N- (2-methoxyphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)322

Compound I-1073-amino-N- (2, 5-dimethoxyphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)352

Compound I-1083-amino-N- (2-methoxy-5-methylphenyl) -6- (pyridin-3-yl) pyrazine-2-carboxamide; MS (ES +)336

Example 4: 2- (3-amino-6- (4- (methylsulfonyl) phenyl) pyrazin-2-yl) -1H-benzo [ d ] imidazol-7-ol (Compound I-109)

Synthesis route D

Compound I-109 was prepared using method a, step 1, then using methods I-C, steps 1-2, then using methods I-D, step 1.

Methods I to D

Step 1: 2- (3-amino-6- (4- (methylsulfonyl) phenyl) pyrazin-2-yl) -1H-benzo [ d ] imidazol-7-ol

A mixture of 3-amino-6- (4-methylsulfonylphenyl) pyrazine-2-carboxylic acid (120mg, 0.4091mmol), diethoxyphosphoryl carbonitrile (73.40mg, 0.4500mmol), triethylamine (124.2mg, 171.1. mu.L, 1.227mmol) and 2, 3-diaminophenol (50.79mg, 0.4091mmol) in DME (5mL) was heated in a microwave at 170 ℃ for 1 hour. The mixture was diluted with Et OAc, washed with water and brine and concentrated in vacuo. The residue was then dissolved in DCM and triturated with ether to give the desired product as a yellow solid (115mg, 74% yield). 1H NMR (400MHz, DMSO)3.6(3H, s), 6.65(1H, d), 7.1-7.18(2H, m), 8.0-8.1(4H, m), 8.6(2H, d), 8.9(1H, s), 9.05(1H, br s), 9.9(1H, s), 12.9(1H, b rs) ppm; MS (ES) ⁺)382

Compounds I-109 to I-121 were prepared using method A, step 1, then method I-C, step 1-2, then method I-D, step 1.

Compound I-1103- (1H-benzo [ d ] imidazol-2-yl) -5-phenylpyrazin-2-amine

1H NMR(400MHz，CDCl₃)1.5(2H，br s)，7.35-7.7(3H，m)，7.5-7.67(3H，m)，7.87(1H，d)，8.02(1H，d)，8.62(1H，s)，10.45(1H，s)ppm；MS(ES⁺)288

Compound I-1112- (3-amino-6- (4- (methylsulfonyl) phenyl) pyrazin-2-yl) -1H-benzo [ d ] imidazole-6-carbonitrile

1H NMR(400MHz，DMSO)3.3(3H，s)，7.7-7.85(2H，m)，8.05(2H，d)，8.43(1H，s)，8.55(2H，d)，9.05(1H，s)，13.55(1H，br s)ppm；MS(ES⁺)389

Compound I-1123- (3H-imidazo [4, 5-b ] pyridin-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine

1H NMR(400MHz，CDCl₃)3.05-3.1(3H，m)，7.4-7.5(2H，m)，7.95-8.05(2H，m)，8.3-8.42(3H，m)，8.8(1H，m)ppm；MS(ES⁺)367

Compound I-1132- (3-amino-6-phenylpyrazin-2-yl) -1H-benzo [ d ] imidazol-7-ol

1H NMR(400MHz，DMSO)6.63(1H，d)，7.05-7.15(2H，m)，7.4-7.44(1H，m)，7.5-7.53(3H，m)，8.3(1H，d)，8.75(2H，s)，9.95(1H，s)，12.9(1H，s)ppm；MS(ES⁺)304

Compound I-1143- (6-chloro-1H-benzo [ d ] imidazol-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine

1H NMR(400MHz，DMSO)3.35(3H，s)，7.25-7.35(1H，m)，7.58-7.62(1H，m)，7.75-7.85(1H，m)，7.95-8.0(2H，m)，8.45-8.52(2H，m)，8.65-8.8(1H，br s)，8.92-8.94(1H，m)，13.2-13.26(1H，m)ppm；MS(ES⁺)400

The compound I-1153- (6-methoxy-1H-benzo [ d ] imidazol-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine

1H NMR(400MHz，DMSO)3.3(3H，s)，3.85(3H，s)，6.9-6.93(1H，m)，7.1-7.3(1H，m)，7.6-7.7(1H，m)，8.05(2H，d)，8.6(2H，d)，8.95(1H，s)，13.1(1H，br s)ppm；MS(ES⁺)396

Compound I-1162- (3-amino-6- (4- (methylsulfonyl) phenyl) pyrazin-2-yl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

1H NMR(400MHz，DMSO)3.28-3.32(3H，m)，3.9-3.95(3H，m)，7.7-7.75(1H，m)，7.9-7.92(1H，m)，8.0-8.1(3H，m)，8.3(0.5H，s)，8.42(0.5H，s)，8.52-8.6(2H，m)，8.7(1H，brs)，9.0-9.03(1H，m)，13.4-13.48(1H，m)ppm；MS(ES⁺)424

Compound I-1173- (6-methyl-1H-benzo [ d ]]Imidazol-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine; 1H NMR (400MHz, DMSO)2.5(3H, s), 3.35(3H, s), 7.05-7.1(1H, m), 7.4-7.7(1H, m), 8.03(2H, d), 8.57(1H, d), 8.95(1H, s), 12.95-13.05(1H, m) ppm; MS (ES)⁺)380

Compound I-1185- (4- (methylsulfonyl) phenyl) -3- (6- (trifluoromethyl) -1H-benzo [ d ]Imidazol-2-yl) pyrazin-2-amine; 1H NMR (400MHz, DMSO)3.3(3H, s), 3.85(3H, s), 6.9-6.93(1H, m), 7.1-7.3(1H, m), 7.6-7.7(1H, m), 8.05(2H, d), 8.6(2H, d), 8.95(1H, s), 13.1(1H, br s) ppm; MS (ES)⁺)434

Compound I-1193- (7-methyl-1H-benzo [ d)]Imidazol-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine; 1H NMR (400MHz in DMSO)2.6-2.7(3H, m), 3.3(3H, s), 7.1-7.25(2H, m), 7.47(1H, d), 8.0-8.1(3H, m), 8.6(1H, d), 8.95(1H, s), 9.05(1H, br s), 12.7(0.2H, br s), 13.1(1H, br) ppm; MS (ES)⁺)380

Compound I-1203- (3H-imidazo [4, 5-c)]Pyridin-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine; 1H NMR (400MHz, DMSO)3.13(3H, s), 7.4-7.45(1H, m), 7.5-7.6(1H, m), 7.8-7.85(2H, m), 8.2-8.25(1H, m), 8.35-8.4(2H, m), 8.7-8.75(1H, m), 8.9(1H, s), 13.25-13.35(1H, m) ppm; MS (ES)⁺)367

The compound I-1213- (1H-benzo [ d ] imidazol-2-yl) -5- (pyridin-3-yl) pyrazin-2-amine

1H NMR(400MHz，CDCl3)7.25-7.35(3H，m)，7.35-7.4(1H，m)，7.52(1H，d)，7.78(1H，d)，8.17(1H，d)，8.55(1H，s)，8.59-8.62(1H，m)，9.17-9.19(1H，m)ppm；MS(ES⁺)289

Example 5: 3- (1H-benzo [ d ] imidazol-2-yl) -5- (3- (methylsulfonyl) phenyl) pyrazin-2-amine (Compound I-122)

Synthesis scheme E

Compound 122 was prepared using method a, steps 1-2, followed by method I-E, steps 1-2.

Methods I to E

Step 1: 3- (1H-benzo [ d ] imidazol-2-yl) -5-bromopyrazin-2-amine

A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (10g, 45.87mmol), benzene-1, 2-diamine (5.45g, 50.46mmol), diethoxyphosphorylcarbonitrile (8.23g, 50.46mmol) and triethylamine (12.79mL, 91.74mmol) in DME (30mL) was heated in a microwave at 170 ℃ for 40 minutes. The mixture was cooled and water was added. The resulting dark precipitate was dissolved in Et OAc and stirred with charcoal for 30 min. After filtration through celite, the filtrate was concentrated in vacuo to give the product as a yellow solid (8.04g, 60% yield). 1H NMR (400MHz, DMSO)7.22-7.32(2H, m), 7.55(1H, d), 7.75(1H, d), 7.8(1H, br s), 8.8(1H, br s), 13.1(1H, s); MS (ES)⁺)291

Step 2: 3- (1H-benzo [ d ] imidazol-2-yl) -5- (3- (methylsulfonyl) phenyl) pyrazin-2-amine

A mixture of 3- (1H-benzimidazol-2-yl) -5-bromo-pyrazin-2-amine (50mg, 0.1723mmol), 3-methylsulfonylphenyl) boronic acid (34.46mg, 0.1723mmol), palladium dichloride, triphenylphosphine (6.047mg, 0.008615mmol) and sodium carbonate (258.5. mu.L, 2M, 0.5169mmol) in DME (625.0. mu.L) was heated in a microwave at 110 ℃ for 1 hour and then at 150 ℃ for 3 hours. The mixture was diluted with Et OAc and washed with water And (4) washing with water. The organic layer was separated and dried (MgSO)₄) And (4) concentrating in vacuum. The residue was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10uM, 100A column, gradient 10% -95% B (solvent A: 0.05% TFA in water, solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The fractions were lyophilized to give the title compound as a solid (37.7mg, 60% yield). 1H NMR (400MHz, CDCl)₃)3.2(3H，s)，7.3-7.45(2H，m)，7.65(1H，d)，7.75(1H，t)，7.85(1H，d)，8.0(1H，d)，8.23(1H，d)，8.65(2H，s)，10.55(1H，s)；MS(ES⁺)366

Compounds I-122 through I-137 were prepared using method A, step 1-2, followed by method I-E, step 1-2.

The compound I-1233- (1H-benzo [ d ] imidazol-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine

1H NMR(400MHz，DMSO)3.4(3H，s)，5.75(2H，s)，7.2-7.38(2H，m)，7.65(1H，d)，7.8(1H，d)，8.05(1H，d)，8.55(1H，d)，8.95(2H，s)，13.3(1H，s)ppm；MS(ES⁺)366

Compound I-1244- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

1H NMR (400MHz, DMSO) d 2.99(s, 3H), 3.02(s, 3H), 7.31(dd, J ═ 3.0, 6.0Hz, 2H), 7.54(d, J ═ 8.4Hz, 2H), 7.72(s, 2H), 8.35(d, J ═ 8.4Hz, 2H) and 8.86(s, 1H) ppm; MS (ES)⁺)359

Compound I-125(3- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (morpholino) methanone; MS (ES +)401

Compound I-1263- (5-amino-6- (1H-benzo [ d)]Imidazol-2-yl) pyrazin-2-yl) phenol; MS (ES)⁺)304

Compound I-127(2- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) methanol

1H NMR(400.0MHz，DMSO)d 4.72(s，2H)，7.27(q，J＝3.0Hz，2H)，7.38-7.47(m2H), 7.55-7.67(m, 5H) and 8.37(s, 1H) ppm; MS (ES)⁺)318

Compound I-1284- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) -N- (3-hydroxypropyl) benzamide; MS (ES +)389

Compound I-1294- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) benzonitrile; MS (ES +)313

Compound I-130N- (4- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) benzyl) acetamide; MS (ES +)359

Compound I-131(5- (5-amino-6- (1H-benzo [ d ]]Imidazol-2-yl) pyrazin-2-yl) -2-fluorophenyl) (morpholino) methanone; MS (ES)⁺)419

Compound I-1324- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) -N- (2-hydroxyethyl) benzamide; MS (ES +)375

Compound I-1334- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide; MS (ES +)428

Compound I-1343- (1H-benzo [ d ] imidazol-2-yl) -5- (4- (pyrrolidin-1-ylsulfonyl) phenyl) pyrazin-2-amine; MS (ES +)421

Compound I-1353- (1H-benzo [ d ]]Imidazol-2-yl) -5- (6-morpholinopyridin-3-yl) pyrazin-2-amine; 1HNMR (400.0MHz, DMSO) d 3.57-3.59(m, 4H), 3.75-3.77(m, 4H), 7.07(d, J ═ 9.1Hz, 1H), 7.28-7.32(m, 2H), 7.71(s, 2H), 8.53(d, J ═ 8.2Hz, 1H), 8.77(s, 1H) and 9.03(d, J ═ 2.0Hz, 1H) ppm; MS (ES) ⁺)374

Compound I-1363- (1H-benzo [ d ] imidazol-2-yl) -5- (2- (piperazin-1-yl) pyridin-4-yl) pyrazin-2-amine; MS (ES +)373

Compound I-1375- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) pyridin-2-ol; MS (ES +)305

Example 6: 3- (5-phenyl-4H-1, 2, 4-triazol-3-yl) -5- (pyridin-3-yl) pyrazin-2-amine (Compound I-138)

Synthesis scheme F

Compound 138 was prepared using method a, step 1, followed by methods I-F, steps 1-4.

Methods I to F

Step 1: 3-amino-6- (pyridin-3-yl) pyrazine-2-carboxylic acid

A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (8g, 34.48mmol), diethyl- (3-pyridyl) borane (6.084g, 41.38mmol), palladium dichloride, triphenylphosphine (1.210g, 1.724mmol) and sodium carbonate (51.70mL, 2M, 103.4mmol) in DME (100mL) was heated at 80 deg.C overnight. The reaction mixture was cooled and Et OAc was added. The resulting precipitate was collected, treated with water, the resulting suspension was heated, and filtered hot. The solution was then cooled and acidified with AcOH to about pH 5. The precipitate was collected, washed with MeOH, and dried to give the product as a yellow powder (6.22g, 83% yield). 1H NMR (400.0MHz, DMSO) d 7.49(dd, J ═ 4.8, 7.4Hz, 1H), 7.60(s, 2H), 8.44(d, J ═ 7.6Hz, 1H), 8.57(d, J ═ 3.7Hz, 1H), 8.97(s, 1H) and 9.27(s, 1H) ppm; MS (ES) ⁺)217

Step 2: 3-amino-6- (pyridin-3-yl) pyrazine-2-carboxylic acid methyl ester

To 3-amino-6- (3-pyridyl) pyrazine-2-carboxylic acid (2g, 9.251mmol) in MeOH (50mL) was added concentrated H₂SO₄(907.3mg, 493.1. mu.L, 9.251mmol) and the mixture was heated to reflux for 2 hours. Removing the solvent in vacuo and adding Na₂CO₃The mixture is neutralized with an aqueous solution. The resulting brown solid was collected by filtration and dried (2.08g, 97% yield). MS (ES)⁺)231

And step 3: 3-amino-6- (pyridin-3-yl) pyrazine-2-carboxylic acid hydrazides

A mixture of methyl 3-amino-6- (3-pyridyl) pyrazine-2-carboxylate (2g, 8.687mmol) and a small amount of MeOH (5mL) in hydrazine (1.392g, 1.363mL, 43.43mmol) was heated at 80 deg.C for 2 hours. Water was added and the product was collected by filtration, washed with methanol and dried to give the product as a brown solid (1.17g, 58% yield). 1H NMR (400.0MHz, DMSO) d4.52(br s, 2H), 7.43(m, 1H), 7.71(s, 2H), 8.54(2H, m), 8.90(1H, s), 9.39(1H, s), 10.16(1H, s) ppm; MS (ES)⁺)231

And 4, step 4: 3- (5-phenyl-4H-1, 2, 4-triazol-3-yl) -5- (pyridin-3-yl) pyrazin-2-amine (Compound 138)

A mixture of 3-amino-6- (3-pyridyl) pyrazine-2-carboxylic acid hydrazide (40mg, 0.173mmol), benzamidine hydrochloride (27.2mg, 0.173mmol), and sodium ethoxide (11.82mg, 0.173mmol) was added to DMF (1mL) in a 5mL microwave vial. The reaction mixture was heated in a microwave at 200 ℃ for 20 min. The mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10uM, 100A column, gradient 10% -95% B (solvent A: 0.05%) Aqueous solution of TFA, solvent B: CH (CH)₃CN) within 16 minutes, 25mL/min]. Fractions were lyophilized to give the title compound as a solid (12.5mg, 20% yield). 1H NMR (500MHz, DMSO) d 7.5(m, 3H), 7.66(m, 1H), 7.94(br s, 2H), 8.16(m, 2H), 8.66(s, 1H), 8.79(br s, 1H), 8.96(s, 1H), 9.52(s, 1H) and 14.94(s, 1H) ppm; MS (ES)⁺)316

Compounds I-138 to I-143 were prepared using method A, step 1, followed by method I-F, steps 1-4.

Compound I-1393- (5- (4- (aminomethyl) phenyl) -4H-1, 2, 4-triazol-3-yl) -5- (pyridin-3-yl) pyrazin-2-amine; MS (ES +)345

Compound I-1403- (5- (3-aminophenyl) -4H-1, 2, 4-triazol-3-yl) -5- (pyridin-3-yl) pyrazin-2-amine; 1H NMR (400.0MHz, DMSO) d6.98-7.03(m, 1H), 7.39(t, J ═ 7.8Hz, 1H), 7.74(s, 2H), 7.82(dd, J ═ 5.2, 8.1Hz, 1H), 8.06(s, 2H), 8.74(dd, J ═ 1.3, 5.2Hz, 1H), 8.96(d, J ═ 7.9Hz, 1H), 9.02(s, 1H), 9.60(s, 1H) and 15.03(br s, 1H) ppm; MS (ES)⁺)331

Compound I-1415- (pyridin-3-yl) -3- (5-m-tolyl-4H-1, 2, 4-triazol-3-yl) pyrazin-2-amine; MS (ES)⁺)330

Compound I-1425- (pyridin-3-yl) -3- (5- (thiophen-2-yl) -4H-1, 2, 4-triazol-3-yl) pyrazin-2-amine; 1H NMR (400.0MHz, DMSO) d 7.22(dd, J ═ 3.8, 4.8Hz, 1H), 7.68-7.73(m, 2H), 7.81(d, J ═ 3.0Hz, 1H), 7.95(s, 2H), 8.69(dd, J ═ 1.2, 4.9Hz, 1H), 8.84(d, J ═ 6.1Hz, 1H), 8.99(s, 1H), 9.55(s, 1H) and 14.96(s, 1H) ppm; MS (ES) ⁺)322

Compound I-1433- (5- (3- (aminomethyl) phenyl) -4H-1, 2, 4-triazol-3-yl) -5- (pyridin-3-yl) pyrazin-2-amine; MS (ES +)345

Example 7: 5- (4- (methylsulfonyl) phenyl) -3- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-amine (Compound I-144) [ there are some compounds from PRV, repeats with the new numbering in the Table! Such as this compound! ]

Synthesis scheme G

Methods I to G

Step 1: 3-amino-6-bromo-N' -hydroxypyrazine-2-carboxamidine

A solution of 3-amino-6-bromo-pyrazine-2-carbonitrile (1g, 5.025mmol) in MeOH (20mL) was cooled to 0 deg.C, treated with hydroxylamine hydrochloride (349.2mg, 5.025mmol) and triethylamine (508.5mg, 700.4. mu.L, 5.025mmol), and the reaction was warmed to ambient temperature. After a 2 hour period, a precipitate was observed and filtered out. The resulting filtrate was evaporated to dryness and triturated with MeOH to give the product again as a pale yellow solid (771mg, 78% yield).

1H NMR (400.0MHz, DMSO) d 5.88(s, 2H), 7.64(br s, 2H), 8.14(s, 1H) and 10.38(s, 1H) ppm; MS (ES)⁺)233

Step 2: 3-amino-N' - (benzoyloxy) -6-bromopyrazine-2-carboxamidine

3-amino-6-bromo-N' -hydroxypyrazine-2-carboxamidine (770mg, 3.318mmol) was suspended in DCM (10mL), triethylamine (369.3mg, 508.7. mu.L, 3.650mmol) was added, followed by benzoyl chloride (513.1mg, 423.7. mu.L, 3.650 mmol). After 1 hour, the solvent was removed in vacuo and the residue triturated with MeOH. The resulting filtrate was filtered to give the product as an off-white solid (779mg, 70% yield).

1H NMR (400.0MHz, DMSO) d 7.18(br s, 2H), 7.55-7.59(m, 2H), 7.69-7.73(m, 1H), 7.89(br s, 2H), 8.28-8.30(m, 2H) and 8.32(s, 1H) ppm; MS (ES)⁺)337

And step 3: 5-bromo-3- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-amine

A mixture of 3-amino-N' - (benzoyloxy) -6-bromopyrazine-2-carboxamidine (575mg, 1.711mmo l) and polyphosphonic acid (2.300mL) was heated at 70 ℃ for 3.5 hours. The resulting solution was diluted with water (20mL) and NaHCO₃Quench and isolate the resulting product by filtration (475mg, 87% yield) as a pale yellow solid.

1H NMR (400.0MHz, DMSO) d 7.48(br s, 2H), 7.67-7.71(m, 2H), 7.76-7.78(m, 1H), 8.26-8.28(m, 2H) and 8.43(s, 1H) ppm; MS (ES)⁺)319

And 4, step 4: 5- (4- (methylsulfonyl) phenyl) -3- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-amine (compound 144)

With Na₂CO₃(471.4 μ L, 2M, 0.9429mmol) 5-bromo-3- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-amine (100mg, 0.3143mmol), (4-methylsulfonylphenyl) boronic acid (94.29mg, 0.4714mmol) and PdCl₂(PPh₃)₂(11.03mg, 0.01572mmol) in DMF (2mL) and the reaction was placed under a nitrogen atmosphere at 110 ℃ in a sealed tubeThe mixture was internally heated for 16 hours. The precipitate was filtered, washed with water and dried in vacuo (83mg, 67% yield).

1H NMR (400.0MHz, DMSO) d 3.27(s, 3H), 7.58(br s, 2H), 7.69-7.73(m, 2H), 7.77-7.81(m, 1H), 8.05(d, J ═ 8.5Hz, 2H), 8.32(dd, J ═ 8.5, 18.0Hz, 4H) and 9.04(s, 1H) ppm; MS (ES)⁺)394

Compounds IIA-1 are also prepared using methods I-G.

Compound IIA-1: 3- (5-phenyl-1, 2, 4-oxadiazol-3-yl) -5- (pyridin-3-yl) pyrazin-2-amine

1H NMR (400.0MHz, DMSO) d 7.32(br s, 2H), 7.38(dd, J ═ 4.3, 8.0Hz, 1H), 7.52-7.56(m, 2H), 7.59-7.64(m, 1H), 8.12-8.14(m, 2H), 8.24-8.27(m, 1H), 8.44(dd, J ═ 1.6, 4.8Hz, 1H), 8.82(s, 1H) and 9.11(d, J ═ 1.8Hz, 1H) ppm; MS (ES)⁺)317

Example 8: 3- (benzo [ d ] thiazol-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine (Compound I-146)

Synthesis scheme H

Compound I-146 was prepared using method a, step 1, then using methods I-C, steps 1-2, then using methods I-H, step 1.

Methods I to H

Step 1: 3- (benzo [ d ] thiazol-2-yl) -5- (4- (methylsulfonyl) phenyl) pyrazin-2-amine (Compound I-146)

3-amino-6- (4-methylsulfonylphenyl) pyrazine-2-carboxylic acid (350mg, 1.193mmol) was heated in thionyl chloride (4.258g, 2.611mL, 35.79mmol) at 70 ℃ for 1 hour. The mixture was concentrated to dryness and washed several times with diethyl ether. The resulting acid chloride (150mg, 0.458mmol) was dissolved in acetonitrile, treated with 2-aminothiophenol (172mg, 1.374mmol) and heated at 70 ℃ for 2 hours. The mixture was diluted with Et OAc and saturated Na ₂CO₃Aqueous solution, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (30-70% EtOAc/hexanes) to give the title compound as a yellow solid (102mg, 52% yield) after trituration with DCM/diethyl ether; 1H NMR (400MHz, CDCl)₃)3.3(3H，s)，7.65-7.8(2H，m)，8.2(1H，d)，8.25-8.3(3H，m)，8.45(2H，d)，8.8(1H，br s)，8.85(1H，s)ppm；MS(ES⁺)383

Example 9: 4- (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenylcarbonyl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (Compound I-147)

Synthesis scheme I

Compound I-147 was prepared using method a, steps 1-2, then using method I-E, step 1, then using method I, steps 1-2.

Method I

Step 1: 4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) benzoic acid

5-bromo-3- (6-methyl-1H-benzimidazol-2-yl) pyrazin-2-amine (1.855g, 6.099mmol), 4-dihydroxybenzoic acid (1.012g, 6.099mmol) and Na₂CO₃(1.293g, 12.20mmol) was suspended in MeCN (30 mL)/water (30 mL). Degassing the mixture (5x N)₂Vacuum cycle), add Pd (PPh)₃)₄(704.8mg, 0.6099 mmol). The mixture was degassed and heated to 90 ℃. No sign of product was observed, whereby a 25mL aliquot was heated in a microwave at 140 ℃ for 1 hour, resulting in product formation. The mixture was cooled and washed with DCM (× 2). The aqueous layer was acidified to pH 4(1M HCl), the resulting precipitate was collected, washed with water, dried under vacuum overnight to give the product as a bright yellow solid (1.30g, 62% yield); MS (ES) ⁺)346

Step 2: 4- (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenylcarbonyl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

To 4- [ 5-amino-6- (6-methyl-1H-benzimidazol-2-yl) pyrazin-2-yl]To a solution of benzoic acid (108mg, 0.3127mmol) in DMSO (1mL) was added tert-butyl 1, 4-diazepan-1-carboxylate (187.9mg, 0.9381mmol), diethyl cyanophosphonate (124.7mg, 114.3. mu.L, 0.6879mmol) and DI PEA (121.2mg, 163.3. mu.L, 0.9381 mmol). The reaction mixture was heated at 80 ℃ overnight, cooled, filtered and the resulting product was used in the next step without further purification (122 mg)75% yield). 1H NMR (400.0MHz, DMSO) d 1.43(s, 9H), 1.59(s, 1H), 1.79(s, 1H), 2.47(s, 3H), 3.39-3.73(m, 8H), 5.80(br s, 2H), 7.13(m, 1H), 7.44-7.49(m, 3H), 7.61(d, 1H), 8.32-8.37(m, 3H) and 8.85(s, 1H) ppm; MS (ES)⁺)528

Compounds I-147 through I-152 were prepared using method A, step 1-2, then method I-E, step 1, then method I, step 1-2.

The compound 148(4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (4- (dimethylamino) piperidin-1-yl) methanone

1H NMR(400.0MHz，DMSO)d 12.9(2H，d)，9.78(1H，s)，8.86(1H，s)，8.37(2H，d)，8.24(1H，br s)，7.61(1H，d)，7.54(2H，d)，7.49(1H，s)，7.13(1H，d)，4.05-5.00(4H，m)，3.79(1H，m)，3.47(1H，m)，3.14(1H，m)，2.79(3H，s)，2.77(3H，s)，2.47(3H，s)，2.02(2H，m)，1.63(2H，m)ppm；MS(ES⁺)456

Compound I-149(4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (piperazin-1-yl) methanone; MS (ES +)414

Compound I-150(4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (4-methylpiperazin-1-yl) methanone

1H NMR(400.0MHz，DMSO)d 12.96(1H，br s)，10.16(1H，s)，8.87(1H，s)，8.40(2H，d)，7.61-7.57(3H，m)，7.49(1H，s)，7.12(1H，d)，5.2-3.81(2H，m)，3.49-3.11(6H，m)，2.85(3H，s)，2.47(3H，s)ppm；MS(ES⁺)428

Compound I-151(4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (4-methyl-1, 4-diazepan-1-yl) methanone

1H NMR(400.0MHz，CD₃OD)d 8.56(1H，s)，8.22(2H，d)，7.55-7.46(3H，m)，7.39(1H，s)，7.05(1H，d)，3.81-3.25(10H，m)，2.90(3H，s)，2.20(3H，s)，2.21-2.07(2H，m)ppm；MS(ES⁺)442

Compound I-1524- (5-amino-6- (1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide; MS (ES +)428

Example 10: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone (Compound I-153)

Synthetic schemes I-J

Methods I to J

Step 1: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone

4- [4- [ 5-amino-6- (6-methyl-1H-benzimidazole-2-yl) pyrazin-2-yl]Benzoyl radical]-1, 4-diazepan-1-carboxylic acid tert-butyl ester (117mg, 0.2218mmol) was dissolved in DCM (3mL) and the mixture was cooled to 0 ℃. TFA (3mL, 38.94mmol) was added and the reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The solvent was evaporated and the residue was dissolved in a mixture of MeCN and water (5mL/5mL) and subjected to Genevac evaporation to give the product (119mg, 99% yield). 1H NMR (400.0MHz, CD) ₃OD)d 2.18-2.04(2H，m)，2.45(3H，s)，3.33(3H，m)，3.44(2H，m)，3.63(2H，m)，3.82(1H，m)，3.96(2H，m)，7.15(1H，d)，7.45(1H，s)，7.55(2H，d)，7.58(1H，s)，8.59(2H，d)，8.59(1H，s)ppm；MS(ES⁺)428

Example 11: 3-amino-6- (4- (4- (dimethylamino) piperidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide (Compound II-10)

Synthetic route II-A

Method II-A: step 1: 3-amino-6-bromopyrazine-2-carboxylic acid methyl ester

A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35g, 54.53mmol) and N-bromo-succinimide (9.705g, 54.53mmol) was stirred in MeCN (100mL) at room temperature overnight. Filtration gave a precipitate, which was washed with MeCN and dried to give the desired product as a yellow solid (11.68g, 92% yield); 1H NMR (400.0MHz, DMSO)3.85(s, 3H), 7.55(brs, 2H) and 8.42(s, 1H) ppm; MS (ES)⁺)233

Step 2: 3-amino-6-bromopyrazine-2-carboxylic acid

And step 3: 3-amino-6-bromo-N-phenylpyrazine-2-carboxamides

A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (3.5g, 16.05mmol), 1' -carbonyldiimidazole (5.205g, 32.10mmol), DIPEA (2.282g, 3.075mL, 17.66mmol) and DMAP (98.04mg, 0.8025mmol) was combined in DMSO (131mL) and stirred for 30mi n. Aniline (1.495g, 1.463mL, 16.05mmol) was then added and the resulting solution was stirred at RT for 18 hours. Water was then added and the product was collected by filtration to give a brown powder (3.5g, 74% yield).

And 4, step 4: 4- (5-amino-6- (phenylcarbamoyl) pyrazin-2-yl) benzoic acid

3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (3.62g, 12.35mmol), 4-dihydroxyborobenzoic acid (2.049g, 12.35mmol) and Na₂CO₃(2.618g, 24.70mmol) of the mixture was suspended in MeCN (60 mL)/water (60 mL). Degassing the mixture (5 x N)₂Vacuum cycle), add Pd (PPh)₃)₄(1.427g, 1.235 mmol). The mixture was degassed and heated to 90 ℃. After 4 hours, the mixture was cooled, concentrated to half the original volume and washed with DCM. The aqueous phase was acidified to pH 4(2M HCl) and the resulting precipitate was collected, washed with water and dried under vacuum overnight to give the product as a bright yellow solid (3.05g, 69% yield). 1H NMR (400MHz, DMSO) d 7.17(1H, t), 7.41(2H, t),7.83(4H，d)，8.03(2H，d)，8.37(2H，d)，9.01(1H，s)，10.45(1H，s)，13.03(1H，br s)ppm；MS(ES+)335

and 5: 3-amino-6- (4- (4- (dimethylamino) piperidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide

N, N-dimethylpiperidin-4-amine (57.54mg, 0.449mmol) is weighed into Greenhouse tubes and treated with a solution of 4- (5-amino-6- (phenylcarbamoyl) pyrazin-2-yl) benzoic acid (50mg, 0.150mmol), CDI (48.51mg, 0.299mmol) and DMAP (1.82mg, 0.015mmol) in DMSO (1mL stock solution). DIPEA (78.2uL, 0.449mmol) was then added and the mixture was stirred at 38 ℃ for 6 hours. The reaction mixture was filtered and the resulting residue was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10uM, 100A column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA, solvent B: CH3CN) over 16 min, 25mL/min ]. Fractions were lyophilized to give the title compound as a solid (54.65, 80% yield). (ES)⁺)445

All of the following compounds were prepared using the above sequence:

compound II-1: 6- (4- (1, 4-diazepan-1-carbonyl) phenyl) -3-amino-N-phenylpyrazine-2-carboxamide 1H NMR (400.0MHz, DMSO) d 1.44-1.47(m, 1H), 1.53-1.58(m, 1H), 2.57-2.61(m, 1H), 2.62-2.69(m, 2H), 2.74-2.80(m, 1H), 3.15-3.20(m, 2H), 3.40-3.46(m, 2H), 6.91-6.96(m, 1H), 7.15-7.19(m, 2H), 7.23-7.28(m, 2H), 7.51(br s, 2H), 7.58-7.60(m, 2H), 8.05-8.08(m, 2H), 8.74 (m, 1H) and 10.20 ppm (m, 2H); (ES)⁺)417

Compound II-2: 3-amino-N-phenyl-6- (4- (2- (pyrrolidin-1-yl) ethylcarbamoyl) phenyl) pyrazine-2-carboxamide; 1H NMR (400MHz in DMSO) d 1.80(4H, vbr s), 3.51(2H, br s), 7.18(1H, t), 7.41(2H, t), 7.81-7.85(4H, m), 7.95(2H, d),8.35(2H，d)，8.65(1H，br s)，9.02(1H，s)，10.44(1H，s)ppm；(ES⁺)431

compound II-3: 3-amino-N-phenyl-6- (4- (2- (piperidin-1-yl) ethylcarbamoyl) phenyl) pyrazine-2-carboxamide 1H NMR (400MHz, DMSO) d 1.30-2.40(2H, m), 1.46-1.53(4H, m), 2.33(4H, m), 2.45(2H, t), 3.37-3.44(2H, m), 7.16(1H, t), 7.41(2H, t), 7.79(2H, br s), 7.81(2H, d), 7.95(2H.d), 8.34(2H, d), 8.48(1H, t), 9.00(1H, s), 10.45(1H, s) ppm; (ES) ⁺)445

Compound II-4: 3-amino-N-phenyl-6- (4- (2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carbonyl) phenyl) pyrazine-2-carboxamide (ES)⁺)471

Compound II-5: 3-amino-6- (4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) phenyl) -N-phenylpyrazine-2-carboxamide; (ES +)419

Compound II-6: 3-amino-N-phenyl-6- (4- (4- (pyrrolidin-1-yl) piperidine-1-carbonyl) phenyl) pyrazine-2-carboxamide (ES)⁺)471

Compound II-7: 3-amino-6- (4- (4-methylpiperazine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; (ES +)417

Compound II-8: 3-amino-N-phenyl-6- (4- (piperazine-1-carbonyl) phenyl) pyrazine-2-carboxamide; (ES +)403

Compound II-9: 3-amino-6- (4- (3- (dimethylamino) pyrrolidine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; (ES +)431

Compound II-11: 3-amino-6- (4- (4- (2-cyanoethyl) piperazine-1-carbonyl) phenyl) -N-phenylpyrazine-2-carboxamide; (ES +)456

Example 12: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone (Compound III-1)

Synthetic route III-A

Process III-A

Step 1: 3-amino-6-bromopyrazine-2-carboxylic acid methyl ester

Step 2: 3-amino-6-bromopyrazine-2-carboxylic acid

A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid methyl ester (5.11g, 22.02mmol) and lithium hydroxide (2.637g, 110.1mmol) in MeOH (20mL) and H2O (20mL) was heated to 90 ℃ for 2 hours. The reaction mixture was cooled, neutralized with HC i and the resulting precipitate was collected by filtration. It was used in the next step without further purification (4.80g, 99% yield).

And step 3: 5-bromo-3- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-amine

A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (5.52g, 25.32mmol), 4-methylbenzene-1, 2-diamine (3.09g, 25.32mmol), diethoxyphosphorylcarbonitrile (4.54, 27.85mmol) and triethylamine (7.06mL, 50.64mmol) in DME (30mL) was heated in a microwave at 170 ℃ for 60 minutes. The mixture was diluted with ethyl acetate, with water and then with NaHCO₃The aqueous solution was then washed with brine. With MgSO₄After drying, the mixture was decolorized with activated carbon and filtered through silica gel. After concentration, the mixture was filtered to give gold crystals (4.005g, 52% yield). MS (ES)⁺)305

And 4, step 4: 4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) benzoic acid

5-bromo-3- (6-methyl-1H-benzimidazol-2-yl) pyrazin-2-amine (1.855g, 6.099mmol), 4-dihydroxybenzoic acid (1.012g, 6.099mmol) and Na₂CO₃(1.293g, 12.20mmol) was suspended in MeCN (30 mL)/water (30 mL). Degassing the mixture (5x N)₂Vacuum cycle), add Pd (PPh)₃)₄(704.8mg, 0.6099 mmol). The mixture was degassed and heated to 90 ℃. No sign of product was observed, whereby a 25mL aliquot was heated in a microwave at 140 ℃ for 1 hour, resulting in product formation. The mixture was cooled and washed with DCM (× 2). The aqueous layer was acidified to pH 4(1M HCl) and the resulting precipitate was collected, washed with water and dried under vacuum overnight to give the product as a bright yellow solid (1.30g, 62% yield). MS (ES)⁺)346

And 5: 4- (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenylcarbonyl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

To 4- [ 5-amino-6- (6-methyl-1H-benzimidazol-2-yl) pyrazin-2-yl]To a solution of benzoic acid (108mg, 0.3127mmol) in DMSO (1mL) was added tert-butyl 1, 4-diazepan-1-carboxylate (187.9mg, 0.9381mmol), diethyl cyanophosphonate (124.7mg, 114.3. mu.L, 0.6879mmol) and DI PEA (121.2mg, 163.3. mu.L, 0.9381 mmol). The reaction mixture was heated at 80 ℃ overnight, cooled, filtered and the resulting product used in the next step without further purification (122mg, 75% yield). 1H NMR (400.0MHz, DMSO) d 1.43(s, 9H), 1.59(s, 1H), 1.79(s, 1H), 2.47(s, 3H), 3.39-3.73(m, 8H), 5.80(br s, 2H), 7.13(m, 1H), 7.44-7.49(m, 3H), 7.61(d, 1H), 8.32-8.37(m, 3H) and 8.85(s, 1H) ppm; MS (ES) ⁺)528

Step 6: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone (Compound III-1)

4- [4- [ 5-amino-6- (6-methyl-1H-benzimidazole-2-yl) pyrazin-2-yl]Benzoyl radical]-1, 4-diazepan-1-carboxylic acid tert-butyl ester (117mg, 0.2218mmol) was dissolved in DCM (3mL) and the mixture was cooled to 0 ℃. TFA (3mL, 38.94mmol) was added and the reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The solvent was evaporated and the residue was dissolved in a mixture of MeCN and water (5mL/5mL) and subjected to Genevac evaporation to give the product (119mg, 99% yield). 1H NMR (400.0MHz, CD)₃OD)d 2.18-2.04(2H，m)，2.45(3H，s)，3.33(3H，m)，3.44(2H，m)，3.63(2H，m)，3.82(1H，m)，3.96(2H，m)，7.15(1H，d)，7.45(1H，s)，7.55(2H，d)，7.58(1H，s)，8.59(2H，d)，8.59(1H，s)ppm；MS(ES⁺)428

The above sequence of steps 1-5 was used to prepare all of the following compounds:

compound III-2: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (4- (dimethylamino) piperidin-1-yl) methanone

Compound III-3: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (piperazin-1-yl) methanone; MS (ES +)414

Compound III-4: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (4-methylpiperazin-1-yl) methanone

Compound III-5: (4- (5-amino-6- (6-methyl-1H-benzo [ d ] imidazol-2-yl) pyrazin-2-yl) phenyl) (4-methyl-1, 4-diazepan-1-yl) methanone

Compound III-6: 4- (5-amino-6- (1H-benzo [ d ]]Imidazol-2-yl) pyrazin-2-yl) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide: MS (ES)⁺)428

Example 1A: 4- (5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (Compound IA-23)

Synthetic route

Compound IA-23

Preparation of Compound IA-23 Using method I V-A, Steps 1-3

Method IV-A:

step 1: 3-amino-6-bromo-N' - (phenylcarbonyl) pyrazine-2-carboxylic acid hydrazide

TBTU (22.09g, 68.80mmol) and triethylamine (4.642g, 6.394mL, 45.87mmol) were added to a suspension of 3-amino-6-bromo-pyrazine-2-carboxylic acid (10g, 45.87mmol) and benzoyl hydrazine (7.494g, 55.04mmol) in DMF (100.0mL), and the resulting solution was stirred at ambient temperature for 48 hours, then poured into water (400mL) with vigorous stirring. It was stirred for 30 minutes, filtered and washed with water. The moist solid was dissolved in hot EtOAc and dried (MgSO₄) Filtration, concentration in vacuo and drying of the resulting solid in vacuo gave the desired product (11.34g, 73% yield). 1H NMR (400.0MHz in DMSO) d7.51(2H, m), 7.61(1H, m), 7.69(2H, br s), 7.92(2H, m), 8.44(1H, s), 10.48(1H, br s), 10.54(1H, br s) ppm; MS (ES) ⁺)338.01

Step 2: 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

Polyphosphoric acid (314g) was heated to 100 ℃ and treated stepwise with 3-amino-N' -benzoyl-6-bromopyrazine-2-carboxylic acid hydrazide (22.5g, 66.94mmol) over a 20 minute period. The reaction was stirred at 110-120 ℃ for 6 hours, then cooled, treated with ice/water and stirred. The resulting solid was filtered and washed with water. It was dissolved in Et OAc, washed with water, adjusted to pH11(NaOH solution), then washed with brine, dried (MgSO)₄) Vacuum concentrating to obtainTo the desired product (13.25g, 62% yield). 1H NMR (400.0MHz in DMSO) d 7.69(3H, m), 7.86(2H, br s), 8.16(2H, m), 8.50(1H, s) ppm; MS (ES)⁺)319.89

And step 3: 4- (5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (150mg, 0.4715mmol), [4- (dimethylcarbamoyl) phenyl group in a mixture of acetonitrile (1.5mL) and water (1.5mL)]Boric acid (91.00mg, 0.4715mmol), sodium carbonate (99.95mg, 0.9430mmol) and palladium, triphenylphosphine (54.48mg, 0.04715mmol) were heated in a microwave at 110 ℃ for 30 min. The reaction was diluted with water and Et OAc and the layers were separated. The combined organic layers were dried (MgSO) ₄) Filtering and vacuum concentrating. The residue was purified by column chromatography (ISCO company)^TM12g column, 0-100% EtOAc/petroleum ether) to give the desired product (102.8mg, 56% yield). 1H NMR (400.0MHz, DMSO) d 2.98(6H, m), 7.55(2H, m), 7.69-7.71(3H, m), 7.83(2H, br s), 8.17-8.20(4H, m), 9.00(1H, s) ppm; MS (ES)⁺)387.13

All of the following compounds were prepared using a procedure analogous to that described above for compounds I A-23.

The compounds IA-905- (4-isopropylsulfinylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 0.95(d, 3H), 1.25(d, 3H), 2.98-3.02(m, 1H), 7.6-8.0(m, 6H), 8.25(d, 2H), 8.35(d, 2H) and 9.05(s, 1H) ppm; MS (ES)⁺)406.2

Compound IA-1125- [4- (azetidin-1-ylsulfonyl) phenyl]-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, CDCl)₃) d2.0-2.2(m, 2H), 3.0-3.2(m, 2H), 3.83-3.9(m, 4H), 7.6-7.7(m, 3H), 8.05(d, 2H), 8.25-8.3(m, 4H) and 8.85(s, 1H) ppm; MS (ES)⁺)435.2

The compound IA-1343- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- (2-phenylphenyl) pyri-dineOxazin-2-amine 1HNMR (400MHz, DMSO) d 7.2-7.28(2H, m), 7.3-7.35(1H, m), 7.45-7.5(1H, m), 7.55-7.6(3H, m), 7.65-7.7(3H, m), 7.75-7.8(1H, m), 7.72(1H, s) and 8.1-8.15(2H, m) ppm; MS (ES) ⁺)392.3

The compound IA-1845- (2-ethylsulfanylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, CDCl)₃) d 1.25(t, 3H), 3.95(q, 2H), 7.4-7.5(m, 2H), 7.5-7.65(m, 5H), 8.25(d, 2H) and 8.6(s, 1H) ppm; MS (ES)⁺)376.2

The compounds IA-2075- (2-oxazol-5-ylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 7.6-7.8(m, 9H), 8.1-8.13(m, 2H), 8.15(s, 1H) and 8.18(s, 1H) ppm; MS (ES)⁺)383.1

The compound IA-2295- (2-isopropylsulfanylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, CDCl)₃) d 1.35(d, 6H), 3.4-3.5(m, 1H), 7.0(br s, 2H), 7.4-7.45(m, 2H), 7.5-7.65(m, 5H), 8.2-8.25(m, 2H) and 8.55(s, 1H) ppm; MS (ES)⁺)390.2

Example 2A: 4- (5-amino-6- (5- (3-fluorophenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (Compound IA-40)

Synthetic route

Compound IA-40

Preparation of Compound IA-40 Using Process IV-B, Steps 1-4

Method IV-B:

step 1: 3-amino-6- (4- (dimethylcarbamoyl) phenyl) pyrazine-2-carboxylic acid methyl ester

Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (625.1mg, 2.694mmol), (4- (dimethylcarbamoyl) phenyl) in a mixture of acetonitrile (3mL) and water (3mL) ]Boric acid (520mg, 2.694mmol), sodium carbonate (571.1mg, 5.388mmol) and palladium, triphenylphosphine (311.3mg, 0.2694mmol) were heated in a microwave at 110 ℃ for 30 min. The reaction was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (2X) and the combined organic layers were dried (MgSO₄) Filtering and vacuum concentrating. The residue was purified by column chromatography (ISCO company)^TM40g column, 0-100% EtOAc/petroleum ether) to give the desired product as a yellow solid (375mg, 46% yield). 1H NMR (400.0MHz, DMSO) d 3.02(3H, s), 3.15(3H, s), 4.04(3H, s), 7.54(2H, m), 7.97(2H, m), 8.71(1H, s) ppm; MS (ES)⁺)301.13

Step 2: 3-amino-6- (4- (dimethylcarbamoyl) phenyl) pyrazine-2-carboxylic acid

To 3-amino-6- [4- (dimethylcarbamoyl) phenyl]To a solution of pyrazine-2-carboxylic acid methyl ester (390mg, 1.299mmol) in MeOH (2.127mL) was added NaOH (649.5. mu.L, 2M, 1.299mmol) in H₂O (2.127mL) solution. The resulting solution was heated to 60 ℃ for 2 hours, then cooled and neutralized with HCl. The resulting precipitate was collected, washed with diethyl ether and dried (340mg, 91% yield). MS (ES)⁺)287.08

And step 3: 4- (5-amino-6- (2- (3-fluorophenylcarbonyl) hydrazinecarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide

3-fluorobenzoyl hydrazine (80.77mg, 0.5240mmol) is added to 3-amino-6- [4- (dimethylcarbamoyl) phenyl]Pyrazine-2-carboxylic acid (150mg, 0.5240mmol), triethylamine (53.02mg, 73.03 μ L, 0.5240mmol) and TBTU (252.4mg, 0.7860mmol) in DMF (3.000mL) was stirred at RT for 2 h. The reaction was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (2X), and the combined organic layers were washed with water (3X) and dried (MgSO)₄) Filtered and concentrated to give the desired product as a yellow solid (172mg, 78% yield). MS (ES)⁺)423.13

And 4, step 4: 4- (5-amino-6- (5- (3-fluorophenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

4- [ 5-amino-6- [ [ (3-fluorobenzoyl) amino ] cooled in an ice bath was worked up with DIPEA (116.6mg, 157.1 μ L, 0.9021mmol) followed by dibromo (triphenyl) phosphane (165.0mg, 0.3909mmol)]Carbamoyl radical]Pyrazin-2-yl radicals]-a suspension of N, N-dimethyl-benzamide (127mg, 0.3007mmo l) in anhydrous acetonitrile (2.540 mL). The reaction mixture was then placed under a nitrogen atmosphere and stirred for 10 minutes. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to give an impure desired product. The material was then purified by reverse phase preparative HPLC [ Waters sunfire c18, 10mM, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected, passed through a sodium bicarbonate column, and lyophilized to give the title compound as a yellow solid (58.4mg, 48% yield). 1H NMR (400.0MHz, DMSO) d 2.98(6H, m), 7.55-7.61(3H, m), 7.73-7.85(3H, m), 7.96(1H, m), 8.02(1H, m), 8.19(2H, m), 9.01(1H, s) ppm; MS (ES)⁺)405.16

All of the following compounds were prepared using a procedure analogous to that described above for compounds I A-40.

The compound IA-1954- [ 5-amino-6- [5- (3-methoxyphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.98(m, 6H), 3.90(s, 3H), 7.28(m, 1H), 7.55-7.57(m, 2H), 7.60-7.65(m, 2H), 7.74(m, 1H), 8.17(m, 2H) and 9.00(1H, s) ppm; MS (ES)⁺)417.17

Compound IA-2334- [ 5-amino-6- [5- [2- (trifluoromethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.98(m, 6H), 7.51(m, 2H), 7.80(brs,1H) 7.93-8.01(m, 2H), 8.09-8.14(m, 3H), 8.19(m, 1H) and 9.03(s, 1H) ppm; MS (ES)⁺)455.12

Example 3A: 4- (5-amino-6- (5- (benzylamino) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (Compound IA-55)

Synthetic route

Compound IA-55

Preparation of Compounds IA-55 Using method IV-C, Steps 1-3

Method IV-C:

Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (6.012g, 25.91mmol), [4- (dimethylcarbamoyl) phenyl ] at 110 ℃ in a mixture of acetonitrile (28.85mL) and water (28.85mL)]Boric acid (5g, 25.91mmol), sodium carbonate (5.492g, 51.82mmol) and Pd (PPh)₃)₄(2.994g, 2.591 mmol). The reaction mixture was cooled. The residual solid was filtered off. The filtrate was diluted with EtOAc and water and the layers were separated. The aqueous layer was acidified to pH 4 (by addition of 1M HCl) then extracted with dichloromethane (3 ×), dried (MgSO)₄) Filtered and concentrated in vacuo to give the product as a yellow solid. The ethyl acetate extract was concentrated in vacuo and combined with the filtered solid. Pre-adsorbed on silica and purified by silica gel column chromatography using a company, eluting with ethyl acetate/petroleum ether (0-100% EtOAc). The product was eluted with 100% EtOAc. The product fractions were combined and concentrated in vacuo to give a yellow solid (1.95g, 50% yield). 1H NMR (400.0MHz, DMSO) d 3.02(3H, s), 3.15(3H, s), 4.04(3H, s), 7.54(2H, m), 7.97(2H, m), 8.71(1H, s) ppm; MS (ES) ⁺)301.13

Step 2: 4- (5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide

To 3-amino-6- [4- (dimethylcarbamoyl) phenyl]To a solution of pyrazine-2-carboxylic acid methyl ester (1.7011g, 5.664mmol) in Et OH (10.21mL) was added hydrazine (726.1mg, 711.2. mu.L, 22.66 mmol). The resulting solution was heated to reflux for 30 minutes and then cooled to RT. The precipitate was filtered off and dried (1.47g, 87% yield). 1H NMR (400.0MHz, DMSO) d 2.96(s, 3H), 3.00(s, 3H), 4.58(d, J ═ 4.4Hz, 2H), 7.46(d, J ═ 8.4Hz, 2H), 8.27-8.29(m, 2H), 8.88(s, 1H) and 10.09(s, 1H) ppm; MS (ES)⁺)301.13

And step 3: 4- (5-amino-6- (5- (benzylamino) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

A mixture of 4- (5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide (75mg, 0.2497mmol), isothiocyanatomethylbenzene (37.26mg, 33.12. mu.L, 0.2497mmol) and dry THF (1.500mL) was stirred at RT for 4 h. The reaction mixture was evaporated to dryness, treated with DCM and then EDC (71.81mg, 0.3746mmol) and the resulting mixture was stirred at RT overnight. The reaction mixture was filtered and the resulting green precipitate was dried in vacuo (78mg, 73% yield). 1HNMR (400.0MHz, DMSO) d 2.96(s, 3H), 3.00(s, 3H), 4.50(d, J ═ 6.1Hz, 2H), 7.29(d, J ═ 7.2Hz, 1H), 7.35-7.42(m, 4H), 7.51-7.53(m, 2H), 7.65 (brs, 2H), 8.06(dd, J ═ 1.5, 6.9Hz, 2H) and 8.81(d, J ═ 12.4Hz, 2H) ppm; MS (ES) ⁺)416.2

All of the following compounds were prepared using procedures analogous to those described above for compounds I A-55.

The compound IA-1034- [ 5-amino-6- [5- (2-methoxyanilino) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 3.03(s, 3H), 3.07(s, 3H), 3.94(s, 3H), 7.07-7.10(m, 1H), 7.15-7.17(m, 2H), 7.59(d, 2H), 7.75(br s, 2H), 8.12-8.19(m, 3H), 8.94(s, 1H) and 10.17 (m, 3H)s，1H)ppm；MS(ES⁺)432.16

Compound IA-1294- [ 5-amino-6- [5- [ [ (1S) -1- (4-chlorophenyl) ethyl ] ethyl]Amino group]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1HNMR (400.0MHz, DMSO) d 1.50(d, 3H), 2.96(s, 3H), 3.01(s, 3H), 4.83(d, 1H), 7.40-7.47(m, 4H), 7.51-7.54(m, 4H), 8.06(d, 2H), 8.81(s, 1H) and 8.90(br s, 1H) ppm; MS (ES)⁺)464.16

The compound IA-1564- [ 5-amino-6- [5- (phenethylamino) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.77(s, 1H), 2.94(t, 4H), 3.00(s, 3H), 3.04(s, 1H), 3.51-3.56(m, 2H), 7.22-7.24(m, 1H), 7.28-7.34(m, 4H), 7.52(d, 2H), 7.61(s, 1H), 8.05-8.07(m, 2H), 8.32(t, 1H) and 8.81(s, 1H) ppm; MS (ES) ⁺)430.2

The compound IA-1634- [ 5-amino-6- [5- (cyclohexylamino) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 1.17-1.19(m, 1H), 1.30-1.35(m, 4H), 1.57-1.60(m, 1H), 1.74-1.76(m, 2H), 1.99(s, 2H), 2.96(s, 3H), 3.00(s, 3H), 3.48(br s, 1H), 7.52(d, 2H), 7.62(br s, 2H), 8.06(d, 2H), 8.20(d, 1H) and 8.81(s, 1H) ppm; MS (ES)⁺)408.22

Compound IA-2544- [ 5-amino-6- [5- (3-cyanoanilino) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.97(s, 3H), 3.01(s, 3H), 7.54(t, 3H), 7.63(t, 1H), 7.75(br s, 1H), 7.91(dd, 2H), 8.09-8.13(m, 3H), 8.91(s, 1H) and 11.51(s, 1H) ppm; MS (ES)⁺)427.15

The compound IA-2784- [6- (5-acetamido-1, 3, 4-oxadiazol-2-yl) -5-amino-pyrazin-2-yl]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d2.20(s, 3H), 2.96(s, 3H), 3.01(s, 3H), 7.54(d, 2H), 7.66(br s, 2H), 8.08(d, 2H), 8.92(s, 1H) and 11.92(s, 1H) ppm; MS (ES)⁺)368.13

The compound IA-2874- [ 5-amino-6- (5-benzoylamino-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d2.96(s, 3H), 3.00(s, 3H), 3.31(s, 1H), 7.52-7.61(m, 4H), 7.69(t, 2H), 8.06-8.12(m, 4H), 8.95(s, 1H) and 12.35(br s, 1H) ppm; MS (ES)⁺)430.14

Example 4A: (4- (5-amino-6- (5-phenyl-1, 3, 4-thiadiazol-2-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone (Compound IA-68)

Synthetic route

Compound IA-68

Compound IA-68 was prepared using method IV-D, step 1-2.

Method IV-D:

step 1: 5-bromo-3- (5-phenyl-1, 3, 4-thiadiazol-2-yl) pyrazin-2-amine

3-amino-6-bromo-pyrazine-2-carboxylic acid (1.000g, 4.588mmol) and phenylthiohydrazide (759.1mg, 4.588mmol) were suspended in acetonitrile (25.00mL), cooled with an ice bath, and treated with dibromo-triphenyl-phosphane (4.453g, 10.55 mmol). The reaction mixture was stirred in an ice bath for 2 hours, then DIPEA (1.778g, 2.396mL, 13.76mmol) was added slowly at 10 ℃. The reaction was stirred for an additional 1 hour at 0-10 deg.C, and the resulting precipitate was isolated by filtration, washed with a little acetonitrile and dried (659mg, 43% yield). MS (ES)⁺)335.93

Step 2: (4- (5-amino-6- (5-phenyl-1, 3, 4-thiadiazol-2-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone

5-bromo-3- (5-phenyl-1,3, 4-Thiadiazol-2-yl) pyrazin-2-amine (70mg, 0.1257mmol) and [4- (4-tert-Butoxycarbonyl-1, 4-diazepan-1-carbonyl) phenyl]Boric acid (43.77mg, 0.1257mmol) (60% pure) was dissolved in dioxane (700.1 μ L), treated with Na2CO3(125.7 μ L, 2M, 0.2514mmol), degassed/sparged with nitrogen (5 ×). The reaction was then treated with palladium, triphenylphosphine (14.53mg, 0.01257mmol), degassed again and heated in a microwave at 140 ℃ for 30 min. The reaction was treated with EtOAc and brine, the organic layer was separated and MgSO₄Drying, filtering and vacuum concentrating. The product was purified by column chromatography, eluting with 50% EtOAc/petroleum ether, then 10% MeOH/DCM to give the desired product, which was dissolved in DCM (2.000mL) and treated with TFA (2.960g, 2.000mL, 25.96 mmol). After stirring for 30 min at RT and concentration, the residue was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected, passed through a sodium bicarbonate column, and lyophilized to give the title compound (42mg, 74% yield). 1H NMR (400.0MHz, DMSO) d 1.60(1H, m), 1.77(1H, m), 2.72-2.39(4H, m-, 3.40(2H, m), 3.60-3.67(2H, m), 7.52(2H, d), 7.58-7.65(3H, m), 7.99(1H, m), 8.00(2H, br s), 8.10-8.14(3H, m), 8.95(1H, s); MS (ES) ⁺)458.07

Example 5: 4- (5-amino-6- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone (compound IA-2)

Synthetic route

Compound IA-2

Compound IA-2 was prepared using method I V-E, steps 1-5.

Methods IV to E

Step 1: 3-amino-6-bromo-N' -hydroxypyrazine-2-carboxamidine

A mixture of 3-amino-6-bromo-pyrazine-2-carbonitrile (1g, 5.025mmol) was dissolved in MeOH (20.00mL) and cooled to 0 ℃. Hydroxylamine hydrochloride (349.2mg, 5.025mmol) and triethylamine (508.5mg, 700.4. mu.L, 5.025mmol) were added and the reaction was warmed to ambient temperature. After 2 hours, the resulting precipitate was filtered off and dried (898mg, 77% yield). MS (ES)⁺)234.89

Step 2: 3-amino-6-bromo-N' - (phenylcarbonyloxy) pyrazine-2-carboxamidine

3-amino-6-bromo-N' -hydroxypyrazine-2-carboxamidine (890mg, 3.836mmol) was suspended in dichloromethane (11.56mL), treated with triethylamine (427.0mg, 588.2. mu.L, 4.220mmol) followed by benzoyl chloride (593.2mg, 489.8. mu.L, 4.220 mmol). The reaction mixture was stirred for 1 hour and concentrated in vacuo. The resulting residue was triturated with methanol to give the desired product as a light yellow solid (891mg, 69% yield). 1H NMR (400.0MHz in DMSO) d 7.55(2H, m), 7.65(1H, m), 7.90(2H, br s), 8.28(2H, m), 8.33(1H, s); MS (ES) ⁺)337.87

And step 3: 5-bromo-3- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-amine

3-amino-N' - (benzoyloxy) -6-bromopyrazine-2-carboxamidine (890mg, 2.648mmol) and polyphosphonic acid (3.560mL) were combined and the reaction was heated to 70 ℃. The polyphosphonic acid (8.900mL) was added and the reaction was stirred at 70 ℃ for an additional 3 hours. The mixture was then cooled to RT, diluted with water and purified by stepwise addition of solid NaHCO₃And (4) neutralizing. The resulting precipitate was isolated by filtration and dried (643mg, 76% yield). 1H NMR (400.0MHz in DMSO) d 7.49(2H, br s), 7.69(2H, m), 7.77(1H, m), 8.28(2H, m), 8.43(1H, s); MS (ES)⁺)319.89

And 4, step 4: 4- (5-amino-6- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-yl) benzoic acid

5-bromo-3- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-amine (200mg, 0.6287mmol), 4-carboxyphenylboronic acid (104.3mg, 0.6287mmol) and Na₂CO₃(133.2mg, 1.257mmol) was suspended in MeCN (3.314 mL)/water (3.314mL), the mixture was degassed (x5) and Pd (PPh)₃)₄(72.65mg, 0.06287 mmol). The reaction was degassed and heated in a microwave at 110 ℃ for 30 minutes. The mixture was concentrated to half its original volume and washed with DCM. The aqueous phase was acidified to pH 4(2M HCl) and the resulting precipitate was collected, washed with water and dried in vacuo (172mg, 76% yield). 1HNMR (400.0MHz, DMSO) d 7.41(2H, br s), 7.69(2H, m), 7.76(1H, m), 7.98(2H, m), 8.09(2H, m), 8.29(2H, m), 8.94(1H, s); MS (ES) ⁺)360.98

And 5: 4- (5-amino-6- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone

Treatment of 4- [ 5-amino-6- (5-phenyl-1, 2, 4-oxadiazol-3-yl) pyrazin-2-yl with 1, 4-diazepane (66.89mg, 0.6678mmol)]Benzoic acid (80mg, 0.2226mmol), CDI (72.19mg, 0.4452mmol), DIPEA (86.31mg, 116.3. mu.L, 0.6678mmol), DMAP (2.719mg, 0.02226mmol) in DMSO (1.370mL) and the resulting solution was stirred at RT overnight. An additional 1 equivalent of 1, 4-diazepane (22.30mg, 0.2226mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was treated with water and the aqueous layer was extracted with Et OAc. The layers were separated and the organic layer was dried (MgSO₄) Concentrated in vacuo, purified by reverse phase HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected, lyophilized to give the title compound as a yellow solid (58.1mg, 39% yield). 1H NMR (400.0MHz, DMSO) d 1.96-2.04(2H, m), 3.25-3.85(8H, m-with water signal), 7.47(2H,br s)，7.60(2H，m)，7.71(2H，m)，7.79(1H，m)，8.16(2H，m)，8.29(2H，m)，8.77(2H，m)，8.97(1H，s)；MS(ES⁺)442.02

example 6A: 4- (5-amino-6- (3-phenylisoxazol-5-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone (compound IIA-3)

Synthetic route

Compound IIA-3

Compound IIA-3 was prepared using method IV-F, steps 1-6.

Method IV-F:

step 1: 5-bromo-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine

(trimethylsilyl) acetylene (1.845g, 2.655mL, 18.78mmol) was added dropwise to 3, 5-dibromopyrazin-2-amine (5g, 19.77mmol), triethylamine (10.00g, 13.77mL, 98.85mmol), copper (I) iodide (451.7mg, 2.372mmol) and Pd (PPh)₃)₄(1.142g, 0.9885mmol) in DMF (25.00mL) and the resulting solution was stirred at RT for 30 min. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and dried (MgSO)₄) And (4) concentrating in vacuum. The residue was purified by column chromatography, eluting with 15% EtOAc/petroleum ether, to give the product as a yellow solid (3.99g, 75% yield). 1H NMR (400.0MHz, DMSO) d 0.30(9H, s), 8.06(1H, s); MS (ES)⁺)271.82

Step 2: N-Boc-N- [ 5-bromo-3- ((trimethylsilyl) ethynyl) pyrazin-2-yl ] carbamic acid tert-butyl ester

5-bromo-3- (2-trimethylsilylethynyl) pyrazin-2-amine (2.85g, 10.5)5mmol) was dissolved in DCM (89.06mL), treated with BOC anhydride (6.908g, 7.272mL, 31.65mmol) and then DMAP (128.9mg, 1.055 mmol). The reaction was stirred at ambient temperature for 2 hours, then with DCM and NaHCO ₃Dilute and separate the layers. The aqueous layer was extracted with DCM and dried (MgSO)₄) Filtering and vacuum concentrating. The resulting residue was purified by column chromatography, eluting with dichloromethane, to give the desired product as a colorless oil (4.95g, 99% yield). 1H NMR (400.0MHz, DMSO) d 0.27(9H, s), 1.42(18H, s), 8.50(1H, s); MS (ES)⁺)472.09

And step 3: n- (5-bromo-3-ethynyl-pyrazin-2-yl) -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

Sodium carbonate (918.5. mu.L, 2M, 1.837mmol) was added to N- [ 5-bromo-3- (2-trimethylsilylethynyl) pyrazin-2-yl]-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (720mg, 1.531mmol) in DMF (2mL) and the resulting solution was heated at 90 ℃ for 20 min. The reaction mixture was cooled to RT, diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and dried (MgSO)₄) Concentration in vacuo afforded the product as a yellow solid (574mg, 94% yield). 1H NMR (400.0MHz, DMSO) d 1.43(18H, s), 3.53(1H, s), 8.55(1H, s); MS (ES)⁺)400.03

And 4, step 4: n- [ 5-bromo-3- (3-phenylisoxazol-5-yl) pyrazin-2-yl ] -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

Triethylamine (50.82mg, 70.00. mu.L, 0.5022mmol) was added to a solution of N- (5-bromo-3-ethynyl-pyrazin-2-yl) -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (200mg, 0.5022mmol) and N-hydroxybenzylidene chloride (78.13mg, 0.5022mmol) in THF (16.00mL) and the reaction mixture was stirred at RT for 1 h. At this time, the reaction mixture was heated at reflux for 3 hours, cooled to RT and concentrated in vacuo. The residue was purified by column chromatography, eluting with 10% EtOAc/petroleum ether, to give the product as a colorless oil that crystallized on standing (182mg, 70% yield). 1H NMR (400.0MHz in DMSO) d 1.41(18H, s), 7 .37(1H，s)，7.52(3H，m)，7.90(2H，m)，8.68(1H，s)；MS(ES⁺)519.05

And 5: 4- (5- (bis (tert-butyloxycarbonyl) amino) -6- (3-phenylisoxazol-5-yl) pyrazin-2-yl) benzoic acid

Reacting N- [ 5-bromo-3- (3-phenylisoxazol-5-yl) pyrazin-2-yl]-N-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (184mg, 0.3379mmol), 4-dihydroxyborobenzoic acid (56.07mg, 0.3379mmol) and Na₂CO₃(71.63mg, 0.6758mmol) suspended in MeCN (2.896 mL)/water (2.896mL), the mixture degassed (x 5), and Pd (PPh)₃)₄(39.05mg, 0.03379 mmol). The reaction was degassed and heated in a microwave at 110 ℃ for 30 minutes. The reaction mixture was concentrated to half its original volume and washed with DCM. The aqueous phase was acidified to pH 4 with (2MHCl) and the resulting precipitate was collected, washed with water and dried in vacuo (120mg, 99% yield). MS (ES)⁺)359.12

Step 6: 4- (5-amino-6- (3-phenylisoxazol-5-yl) pyrazin-2-yl) phenyl) (1, 4-diazepan-1-yl) methanone

To 4- [ 5-amino-6- (3-phenylisoxazol-5-yl) pyrazin-2-yl]To a solution of benzoic acid (120mg, 0.3349mmol), CDI (108.6mg, 0.6698mmol), DIPEA (129.9mg, 175.1. mu.L, 1.005mmol), DMAP (4.091mg, 0.03349mmol) in DMSO (2.054mL) was added tert-butyl 1, 4-diazepan-1-carboxylate (201.3mg, 1.005mmol), and the resulting solution was stirred at RT for 3 hours. At this point water was added, the aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO ₄) And (4) concentrating in vacuum. The resulting residue was dissolved in DCM (3.000mL), treated with TFA (763.7mg, 516.0 μ L, 6.698mmol) and the mixture was stirred at RT overnight. The mixture was concentrated in vacuo, the residue dissolved in dichloromethane (5mL) and NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (MgSO₄) Concentrated in vacuo, purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95%B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected, lyophilized to give the title compound as a yellow solid (68.7mg, 37% yield). 1H NMR (400.0MHz, DMSO) d 1.95(2H, m), 3.25-3.96(8H, m fraction hidden by water peak), 7.08(2H, br s), 7.54-7.61(5H, m), 7.78(1H, s), 8.03-8.05(2H, m), 8.19(2H, m), 8.72(2H, br s), 8.89(1H, s); MS (ES)⁺)441.21

Example 7: 5- (pyridin-3-yl) -3- (5- (thiophen-2-yl) -4H-1, 2, 4-triazol-3-yl) pyrazin-2-amine (Compound IIIA-4)

Synthetic route

Compound IIA-4

Compound IIIA-4 was prepared using method I V-G, steps 1-5.

Methods IV-G:

step 1: 3-amino-6-bromopyrazine-2-carboxylic acid methyl ester

A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35g, 54.53mmol) and N-bromo-succinimide (9.705g, 54.53mmol) was stirred in MeCN (100mL) at room temperature for 16 h. Filtration gave a precipitate, which was washed with MeCN and dried in vacuo to give the desired product as a yellow solid (11.68g, 92%). 1H NMR (400.0MHz, DMSO) d 3.85(3H, s), 7.55(2H, br s), 8.42(1H, s); MS (ES) ⁺)233.78

Step 2: 3-amino-6- (pyridin-3-yl) pyrazine-2-carboxylic acid

Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (8g, 34.48mmol), diethyl- (3-pyridyl) borane (6.084g, 41.38mmol), dichloropalladium, triphenylphosphine (1.210g, 1.724mmol), sodium carbonate (51.70mL, 2M, 103.4 mm) in DME (100mL)ol) was heated at 80 ℃ for 16 hours. The reaction mixture was cooled, treated with EtOAc, and the resulting precipitate was isolated by filtration. Water was added to the solid, then the suspension was heated, filtered hot, then the solution was cooled, and then acidified (AcOH) to about pH 5. The precipitate was collected, washed with MeOH, and dried in vacuo (6.23g, 84% yield). 1H NMR (400.0MHz, DMSO) d 7.47(1H, m), 7.60(2H, br s), 8.42-8.57(2H, m), 8.97(1H, s), 9.26(1H, m); MS (ES)⁺)216.89

And step 3: 3-amino-6- (pyridin-3-yl) pyrazine-2-carboxylic acid methyl ester

To 3-amino-6- (3-pyridyl) pyrazine-2-carboxylic acid (2g, 9.251mmol) in MeOH (50mL) was added concentrated H₂SO₄(907.3mg, 493.1. mu.L, 9.251mmol) and the mixture was heated to reflux for 2 hours. Removing the solvent in vacuo and adding Na₂CO₃The mixture was neutralized with aqueous solution and the resulting solid was collected by filtration and dried to give the desired product (2.08g, 97% yield). MS (ES) ⁺)231.87

And 4, step 4: 3-amino-6- (pyridin-3-yl) pyrazine-2-carboxylic acid hydrazides

Methyl 3-amino-6- (3-pyridyl) pyrazine-2-carboxylate (2g, 8.687mmol) in hydrazine (1.392g, 1.363mL, 43.43mmol) was heated with the addition of a small amount of MeOH (5mL) at 80 ℃ for 2 hours. The reaction was treated with water and the product was collected by filtration, washed with household energy and dried to give the desired product as a brown solid (1.17g, 58% yield). 1HNMR (400.0MHz, DMSO) d 7.43(1H, m), 7.47(2H, br s), 8.54(2H, m), 8.90(1H, s), 9.38(1H, m), 10.16(1H, br s); MS (ES)⁺)231.96

And 5: 5- (pyridin-3-yl) -3- (5- (thiophen-2-yl) -4H-1, 2, 4-triazol-3-yl) pyrazin-2-amine

3-amino-6- (3-pyridyl) pyrazine-2-carboxylic acid hydrazide (40mg, 0.173mmol), thiophene-2-carboxamidine (21.92mg, 0.173mmol), and sodium ethoxide (11.82mg, 0.173mmol) were added to a microwave vial. DMF (1mL) was then added, the vial was sealed, and the mixture was heated in a microwave at 160 ℃ for 40 minutes. Filtering the mixtureThe reaction mixture was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected and lyophilized to give the title compound (23.4mg, 31% yield). 1H NMR (400.0MHz, DMSO-d6) d 14.96(s, 1H), 9.55(s, 1H), 8.99(s, 1H), 8.84(d, J ═ 6.1Hz, 1H), 8.69(dd, J ═ 1.2, 4.9Hz, 1H), 7.95(s, 2H), 7.81(d, J ═ 3.0Hz, 1H), 7.73-7.68(m, 2H) and 7.22(dd, J ═ 3.8, 4.8Hz, 1H) ppm; MS (ES) ⁺)323.10

Example 8A: n- (2- (5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) phenyl) acetamide (Compound IA-267)

Compound IA-267

Compound IA-267 was prepared using method IV-a, step 1-2, followed by method IV-H, step 1.

Method II-H: step 1: n- (2- (5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) phenyl) acetamide

5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (100mg, 0.31mmol), 2-acetamidophenylboronic acid (56.25mg, 0.31mmol), tetrakis (triphenylphosphine) palladium (18.17mg, 0.015mmol) and Na₂CO₃An aqueous solution (471 μ L, 2M aqueous solution) was added to a 10mL microwave vial. Dioxane (3mL) was then added and the vial was sealed. The reaction mixture was heated in a microwave at 150 ℃ for 30 min. At this time, methanol was added and the reaction mixture was filtered. The solid was then washed with water (5mL) and MeOH (5mL) and dried in vacuo to give the product (31.0mg, 28% yield); 1H NMR (400.0)MHz, DMSO) d2.04(s, 3H), 7.26(t, 1H), 7.44-7.40(m, 1H), 7.69-7.67(m, 4H), 7.80(d, 2H), 8.15-8.13(m, 3H), 8.73(s, 1H) and 10.76(s, 1H) ppm; MS (ES)⁺)373.0

The following compounds were all prepared using the procedure described above for compounds I A-267.

Compound I A-751H NMR (400.0MHz, DMSO)3.25(s, 3H), 7.63(s, 1H), 7.63(dd, 2H), 7.74(t, 3H), 7.90(dd, 1H), 8.09(dd, 2H), 8.40(dd, 1H), 8.54(t, 1H) and 9.00(s, 1H) ppm; MS (ES)⁺)394.0

The compound IA-895- (4-methylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)393.0

The compound IA-935- (1-naphthyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)365.0

The compound IA-945- (2- (dimethylamino) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)359.0

Compound IA-963- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- [3- (trifluoromethyl) phenyl]Pyrazin-2-amine; MS (ES)⁺)384.0

The compound IA-1003- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]A benzamide; MS (ES)⁺)359.0

The compound IA-1043- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- (3-thienyl) pyrazin-2-amine; MS (ES)⁺)322.0

The compound IA-1052- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Methyl benzoate; 1H NMR (400.0MHz, DMSO) d 3.61(s, 3H), 7.56(m, 1H), 7.65-7.72(m, 7H), 7.87(d, 1H), 8.16(m, 2H) and 8.72(s, 1H) ppm; MS (ES)⁺)374.0

The compound IA-1101- [4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ]Phenyl radical]An ethanone; MS (Mass Spectrometry)(ES⁺)358.0

The compound IA-1165- (4-isopropylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; 1H NMR (400.0MHz, DMSO) d 1.20(d, 6H), 3.47(t, 1H), 7.66-7.72(m, 3H), 7.98(d, 4H), 8.17-8.19(m, 2H), 8.40(dd, 2H) and 9.60(s, 1H) ppm; MS (ES)⁺)422.0

The compound IA-1185- (2- ((dimethylamino) methyl) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)373.0

Compound IA-1255- [2- (methoxymethyl) phenyl]-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)360.0

The compound IA-1372- [2- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Phenyl radical]Ethanol; 1H NMR (400.0MHz, DMSO) d 2.89(t, 2H), 3.74(s, 2H), 4.61(s, 1H), 7.32-7.43(m, 3H), 7.47-7.49(m, 1H), 7.61-7.69(m, 5H), 8.13-8.16(m, 2H) and 8.49(s, 1H) ppm; MS (ES)⁺)360.0

The compound IA-1415- (4-pyridinyl) -3- [5- (2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine; 1H NMR (400.0MHz, DMSO) d 7.22(t, 1H), 7.38(t, 1H), 7.80-7.82(m, 1H), 8.04-8.09(m, 4H), 8.70(dd, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)323.1

The compound IA-144N- [3- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ]Phenyl radical]A methanesulfonamide; MS (ES)⁺)408.0

The compound IA-1495- (4-ethylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)408.0

Compound I A-1503- (5-phenyl-1, 3, 4-oxadiazole-2-yl) -5- [3- (trifluoromethoxy) phenyl]Pyrazin-2-amine; MS (ES)⁺)400.0

Compound IA-1695- [4- (2-dimethylaminoethylsulfonyl) phenyl]-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl)Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d2.81(s, 6H), 3.43-3.40(m, 2H), 3.89-3.93(m, 2H), 7.68-7.73(m, 3H), 7.90(br s, 2H), 8.07(d, 2H), 8.17-8.19(m, 2H), 8.45(d, 2H) and 9.10(s, 1H) ppm; MS (ES)⁺)451.0

The compound IA-1705- (3-furyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)306.0

The compound IA-1743- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- [2 (-trifluoromethyl) phenyl]Pyrazin-2-amine; MS (ES)⁺)384.0

The compound IA-1765- (2-bromophenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)393.0

The compound IA-1825- (m-tolyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)330.0

The compound IA-1905- (2-methylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)394.0

The compound IA-1973- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- [4- (4-piperidinylsulfonyl) phenyl ]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.76-1.70(m, 2H), 2.08(d, 2H), 2.89(d, 2H), 3.37(d, 2H), 3.66(d, 1H), 7.70(d, 2H), 7.82(s, 1H), 7.86(s, 1H), 7.98(d, 2H), 8.13(s, 1H), 8.18(d, 2H), 8.44(d, 2H), 8.63(s, 1H) and 9.08(s, 1H) ppm; MS (ES)⁺)463.0

The compound IA-202[3- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Phenyl radical]Methanol; MS (ES)⁺)346.0

The compound IA-2105- (1-ethylpyrazol-4-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)334.0

The compound IA-2163- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- (8-quinolinyl) pyrazin-2-amine; 1H NMR (400.0MHz in DMSO) d 7.63-7.71(m, 4H), 7.82(t, 3H), 8.10-8.15(m,3H) 8.26(m, 1H), 8.53(m, 1H), 9.01(dd, 1H) and 9.14(s, 1H) ppm; MS (ES)⁺)366.023

The compound IA-2184- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]A benzamide; MS (ES)⁺)359.0

The compound IA-2212- [2- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Phenyl radical]Acetonitrile; MS (ES)⁺)355.0

The compound IA-2305- (2-methylsulfanylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)362.0

The compound IA-2415- (2-methylsulfinylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES) ⁺)378.0

The compound IA-2442- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]-N, N-dimethyl-benzamide; MS (ES)⁺)387.0

The compound IA-247N- [4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Phenyl radical]An acetamide; MS (ES)⁺)373.0

The compound IA-2491- [3- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Phenyl radical]An ethanone; 1H NMR (400.0MHz, DMSO) d 2.70(s, 3H), 7.67-7.71(m, 4H), 8.00-8.02(m, 1H), 8.17(dd, 2H), 8.39(d, 1H), 8.64(d, 1H) and 9.05(s, 1H) ppm; MS (ES)⁺)358.0

The compound IA-2523- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]A benzonitrile; MS (ES)⁺)341.0

The compound IA-2533- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- (2-vinylphenyl) pyrazin-2-amine; MS (ES)⁺)342.0

The compound IA-2595- (benzothien-7-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine; MS (ES)⁺)371.0

The compound IA-2603- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- (5-quinolinyl) pyrazin-2-amine; MS (ES)⁺)366.0

The compound IA-2662- [2- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Phenyl radical]An acetamide; 1H NMR (400.0MHz, DMSO) d 3.64(s, 2H), 6.88(s, 1H), 7.40(dd, 4H), 7.51-7.53(m, 1H), 7.62(s, 1H), 7.67(dd, 4H), 8.12(d, 2H) and 8.49(s, 1H) ppm; MS (ES) ⁺)373.0

The compound IA-2713- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- (2-piperazin-1-yl-4-pyridinyl) pyrazin-2-amine; MS (ES)⁺)400.0

The compounds IA-2745- (4-methylsulfinylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 2.81(s, 3H), 7.69(d, 3H), 7.83(d, 3H), 8.16-8.19(m, 2H), 8.30-8.33(m, 2H) and 9.02(s, 1H) ppm; MS (ES)⁺)377.0

Example 9A: 4- [ 5-amino-6- [5- (2-chloroanilino) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-151)

Synthetic route

Compound IA-151

Compound IA-151 was prepared using method IV-C, step 1-2, followed by method IV-I, step 1.

Process IV-I

Step 1: 4- [ 5-amino-6- [5- (2-chloroanilino) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

A solution of 2-chloroaniline (31.85mg, 41.15. mu.L, 0.2497mmol) in dichloromethane (2mL)Slowly added dropwise to a solution of 1, 1' -thiocarbonyldiimidazole (53.39mg, 0.2996mmol) in dichloromethane (1.5mL) and the resulting solution was stirred at room temperature for 1 h. 1, 1' -Thiocarbonyldiimidazole (8.9mg, 0.05mmol) was added further and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3 × 5 mL). With MgSO ₄The organic extracts were dried, filtered and evaporated to dryness to give a yellow solid. The solid was redissolved in dichloromethane (1.5mL), 4- (5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide (75mg, 0.2497mmol) was added, and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness and then triturated with Et OAc/petrol/ether to give 4- [ 5-amino-6- [ [ (2-chlorophenyl) aminothiocarbonylamino as a yellow solid]Carbamoyl radical]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide. This was redissolved in dichloromethane (1.5mL), EDC (71.81mg, 0.3746mmol) was added, and the resulting solution was heated at 40 ℃ for 3 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the solid was triturated with EtOAc and petroleum ether to give the product as a yellow solid (28.9mg, 26% yield); 1H NMR (400.0MHz, DMSO) d 2.96(s, 3H), 3.01(s, 3H), 7.15-7.25(m, 1H), 7.40-7.49(m, 1H), 7.53(d, 3H), 7.70(br s, 2H), 8.11(d, 3H), 8.89(s, 1H) and 10.45(s, 1H) ppm; MS (ES)⁺)436.11

Example 10A: 4- [ 5-amino-6- [5- (p-tolyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-263)

Synthetic route

Compound IA-263

Compound IA-263 was prepared using method IV-B, step 1-2, followed by method IV-J, step 1.

Process IV-J

Step 1: 4- [ 5-amino-6- [5- (p-tolyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

Reacting 4- [ 5-amino-6- [ [ (4-methylbenzoyl) amino group]Carbamoyl radical]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide (90mg, 0.2151mmol) and POCl₃(3.298g, 2.005mL, 21.51mmol) was heated at 110 ℃ for 2 h. After this time, the reaction mixture was cooled to room temperature and ice was added. Once the ice had completely melted, the reaction mixture was extracted with dichloromethane (3X 5mL) and MgSO₄The combined organic layers were dried and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Product fractions were combined and lyophilized to give the product as a yellow solid (21.2mg, 20% yield); 1H NMR (400.0MHz, DMSO) d 2.22(s, 3H), 2.75(m, 6H), 7.26(m, 2H), 7.32(m, 2H), 7.58(br s, 2H), 7.83(m, 2H), 7.95(m, 2H) and 8.77(1H, s); MS (ES) ⁺)401.15

The following compounds were all prepared using the procedure described above for compounds I A-263.

The compound IA-1354- [ 5-amino-6- [5- (1-methylpyrrol-2-yl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.97(m, 6H), 4.06(s, 3H), 6.30(m, 1H), 7.03(m, 1H), 7.26(m, 1H), 7.53-7.55(m, 2H), 7.77(br s, 2H), 8.15(m, 2H) and 8.97(1H, s) ppm; MS (ES)⁺)390.14

Example 11A: 4- [ 5-amino-6- [5- (azetidin-1-yl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-192)

Synthetic route

Compounds IA-192

Compound IA-192 was prepared using method IV-C, step 1-2, followed by method IV-K, step 1-2.

Process IV-K

Step 1: 4- (5-amino-6- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

DIPEA (86.08mg, 116.0 μ L, 0.6660mmol) was added to a solution of 4- (5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide (100mg, 0.3330mmol) in DCM (6.500mL) under a nitrogen atmosphere. A solution of triphosgene (39.53mg, 0.1332mmol) in DCM (100.0. mu.L) was then added dropwise to the stirred solution. The reaction mixture was stirred at rt for 2 h. The reaction mixture was filtered and the resulting solid was dried in vacuo to give the product (106, gmg, 98% yield); 1H NMR (400.0MHz, DMSO) d 2.96(s, 3H), 3.00(s, 3H), 7.33(br s, 2H), 7.52(d, 2H), 8.09(d, 2H), 8.89(s, 1H) and 12.98(br s, 1H) ppm; MS (ES) ⁺)327.12

Step 2: 4- [ 5-amino-6- [5- (azetidin-1-yl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

DIPEA (38.44mg, 51.81. mu.L, 0.2974mmol), azetidine (8.490mg, 0.1487mmol) and bromo (trispyrrolidin-1-yl) phosphonium hexafluorophosphate (76.27mg, 0.1636mmol) were added to a solution of 4- (5-amino-6- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (50mg, 0.1487mmol) in DMF (485.1. mu.L) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was filtered, purified by preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were concentrated in vacuo and triturated with dichloromethane/ether to give the product (8.6mg, 15% yield); 1HNMR (400.0MHz, DMSO) d 2.96(s, 3H), 3.00(s, 6H), 4.25(t, 4H), 7.52(dd, 2H), 7.65(br s, 1H), 8.04-8.06(m, 2H) and 8.83(s, 1H) ppm; MS (ES)⁺)366.21

The following compounds were all prepared using the procedure described above for compounds I A-192.

The compound IA-2504- [ 5-amino-6- [5- (N-methylanilino) -1, 3, 4-oxadiazol-2-yl ]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide; MS (ES)⁺)416.18

Example 12A: 4- [ 5-amino-6- [5- (2-furyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-115)

Synthetic route

Compounds IA-115

Compound IA-115 was prepared using method IV-B, step 1-2, followed by method IV-L, step 1.

Process IV-L

Step 1: 4- [ 5-amino-6- [5- (2-furyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

Dibromo (triphenyl) phosphane was added to 3-amino-6- [4- (dimethylcarbamoyl) phenyl group at room temperature]Pyrazine-2-carboxylic acid (100mg, 0.35mmol) and furan 2-carboxylic acid hydrazide (44.1mg, 0.35mmol) in acetonitrile (3.0 mL). A bright yellow solution was observed. The resulting solution was allowed to stand at room temperatureStirring for 30 min. Thereafter, DIPEA (304. mu.L, 1.75mmol) was added dropwise and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered to give a yellow solid. The solid was purified by preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were freeze-dried to give the product as a yellow solid (67.6mg, 51% yield); 1H NMR (400.0MHz, DMSO) d 2.97(m, 6H), 6.87(m, 1H), 7.54-7.56(m, 3H), 7.57(br s, 2H), 8.15(m, 3H) and 8.98(1H, s) ppm; MS (ES) ⁺)377.17

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-115.

The compound IA-714- [ 5-amino-6- [5- (o-tolyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d2.74(s, 3H), 2.98(m, 6H), 7.48-7.62(m, 5H), 7.80(br s, 2H), 8.07(m, 1H), 8.15(m, 2H) and 8.99(1H, s) ppm; MS (ES)⁺)401.21

The compound IA-874- [ 5-amino-6- [5- (4-hydroxyphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.98(m, 6H), 7.04(m, 2H), 7.54(m, 2H), 7.76(br s, 2H), 8.01(m, 2H), 8.16(m, 2H), 8.97(s, 1H) and 10.42(s, 1H) ppm; MS (ES)⁺)403.16

The compound IA-1014- [ 5-amino-6- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d1.14-1.18(m, 2H), 1.22-1.25(m, 2H), 2.40(m, 1H), 3.01(m, 6H), 7.54(m, 2H), 7.68(br s, 2H), 8.10(m, 2H) and 8.93(s, 1H) ppm; MS (ES)⁺)351.17

The compound IA-1574- [ 5-amino-6- [5- (4-methoxyphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.98(m, 6H), 3.89(s, 3H), 7.22(m, 2H), 7.54(m, 2H), 7.76(br s, 2H), 8.10(m, 2H), 8.16(m, 2H) and 8.98(s, 1H) ppm; MS (ES) ⁺)417.18

The compound IA-1674- [ 5-amino-6- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide MS (ES)⁺)407.18

The compound IA-2054- [ 5-amino-6- [5- (2-iodophenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d2.96(m, 6H), 7.43(m, 1H), 7.52(m, 2H), 7.69(m, 1H), 7.81(br s, 2H), 7.96(m, 1H), 8.16(m, 2H), 8.20(m, 1H) and 9.01(s, 1H) ppm; MS (ES)⁺)513.01

The compound IA-2374- [ 5-amino-6- [5- (m-tolyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.53(s, 3H), 3.05(m, 6H), 7.57-7.65(m, 4H), 7.84(br s, 2H), 8.04(m, 2H), 8.23(m, 2H) and 9.05(s, 1H) ppm; MS (ES)⁺)401.2

The compound IA-2424- [ 5-amino-6- [5- (2-methoxyphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.97(m, 6H), 3.97(s, 3H), 7.19-7.23(dt, 1H)7.35(m, 1H), 7.56(m, 2H), 7.65-7.70(m, 1H), 7.77(br s, 2H), 7.99(dd, 1H), 8.14(m, 2H) and 8.98(s, 1H) ppm; MS (ES)⁺)417.19

The compound IA-2454- [ 5-amino-6- [5- (5-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl ]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.60(s, 3H), 2.98(m, 6H), 7.08(d, 1H), 7.53(m, 2H), 7.74(br s, 2H), 7.82(m, 1H), 8.15(m, 2H) and 8.97(1H, s) ppm; MS (ES)⁺)407.12

Compound IA-2624- [ 5-amino-6- [5- (3-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d2.98(m, 6H), 7.53(m, 2H), 7.75-7.77(m, 3H), 7.89(m, 1H), 8.17(m, 2H), 8.57(m, 1H) and 8.98(s, 1H) ppm; MS (ES)⁺)393.12

Example 13A: 4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] -3- (difluoromethyl) -N, N-dimethyl-benzamide (compound IA-126)

Synthetic route

Compound IA-126

Compound IA-126 was prepared using method IV-a, step 1-3, followed by method IV-M, step 1.

Method IV-M

Step 1: 4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] -3- (difluoromethyl) -N, N-dimethyl-benzamide

LiOH (495.9 μ L of a 1M aqueous solution, 0.4959mmol) was added to 4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]A suspension of methyl-3- (difluoromethyl) benzoate (70mg, 0.1653mmol) in THF (5mL) and methanol (2 mL). The reaction mixture was stirred at room temperature for 4h, then concentrated in vacuo. The residue was acidified to pH2 by addition of 1M HCl. The precipitate formed was then filtered and washed with water, ethyl acetate and diethyl ether. The solid was dissolved in DMF (2mL), TBTU (79.63mg, 0.2480mmol) and DIPEA (64.09mg, 86.37. mu.L, 0.4959mmol) were added followed by a solution of N-methyl methylamine (495.9. mu.L, 1M, 0.4959mmol) in THF. The resulting mixture was stirred at room temperature for 2h, diluted with ethyl acetate (5mL), washed with water (2 × 5mL) and concentrated in vacuo. The residue was purified by preparative HPLC [ waters sunfire C18, 10mM, Column, gradient 10% -95% B (solvent a:aqueous 0.05% TFA; solvent B: CH (CH)₃CN) within 16 minutes, 25mL/min]. Freeze-drying the product fractions to give the product as a solid (29.6mg, 40% yield); 1H NMR (400.0MHz, DMSO) d 3.0(d, 6H), 7.6-7.7(m, 4H), 7.82(s, 1H), 7.9(d, 2H), 8.15-8.18(m, 2H) and 8.7(s, 1H) ppm; MS (ES)⁺)437.2

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-126.

The compound IA-1484- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]-3- (2-fluorovinyl) -N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 3.05(d, 6H), 6.15(dd, 0.5H), 6.85-6.95(m, 1H), 7.1(d, 0.25H), 7.45-7.55(m, 2H), 7.6-7.7(m, 5H), 7.8(br s, 2H), 8.1-8.15(m, 2H) and 8.45-8.48(m, 1H) ppm; MS (ES)⁺)431.2

The compound IA-1614- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]-N, N-dimethyl-3-oxazol-5-yl-benzamide 1H NMR (400.0MHz, DMSO) d 3.02(d, 6H), 7.6-7.75(m, 4H), 7.75-7.8(m, 3H), 8.1(d, 2H), 8.19(s, 1H) and 8.19(s, 1H) ppm; MS (ES)⁺)454.1

Example 14A: 5- (2-ethynylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (compound IA-194)

Synthetic route

Compound IA-194

Compound IA-194 was prepared using method IV-a, step 1-2, followed by method IV-N, step 1-3.

Method IV-N

Step 1: 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yliminodicarbonate di-tert-butyl ester

5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (4g, 12.57mmol) was suspended in DCM (59.76mL), THF (59.76mL) and DMAP (153.6mg, 1.257mmol) were added, di-tert-butyl dicarbonate (8.230g, 8.663mL, 37.71mmol) was added in portions, and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 10-20% EtAc/gasoline to give the product as a cream solid (5.72g, 88% yield); 1H NMR (400.0MHz, DMSO) d1.29(s, 18H), 7.69(d, 3H), 8.13(d, 2H) and 9.17(s, 1H) ppm

Step 2: tert-butyl-5- (2-bromophenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl (tert-butoxycarbonyl) carbamate

Mixing (2-bromophenyl) boronic acid (100mg, 0.4979mmol) and N- [ 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]A mixture of tert-butyl-N-tert-butoxycarbonyl-carbamate (258.1mg, 0.4979mmol), potassium carbonate (206.5mg, 1.494mmol) and palladium triphenylphosphine (13.06mg, 11.54. mu.L, 0.04979mmol) in DMF (3mL) was heated at 50 ℃ for 1 h. The reaction mixture was cooled to room temperature and passed through Celite ^TMThe pad is filtered. The pad was washed with ethyl acetate (1X 10mL), the combined filtrates were washed with water (2X 10mL) and brine (1X 10mL), MgSO₄Dried and concentrated to give the product as a solid, which was used in the next step without further purification.

And step 3: 5- (2-ethynylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

Reacting N- [5- (2-bromophenyl) -3- (5-phenyl-1, 3, 4-oxadiazole-2-yl) pyrazin-2-yl]A suspension of-N-tert-butyloxycarbonyl-carbamic acid tert-butyl ester (100mg, 0.1682mmol), copper iodide (9.612mg, 0.05047mmol), palladium dichloride, triphenylphosphine (35.42mg, 0.05046mmol), triethylamine (211.0. mu.L, 1.514mmol) and ethynyl (trimethyl) silane (85.58. mu.L, 0.6056mmol) was heated in toluene (10mL) at 60 ℃ for 1 h. The reaction mixture was cooled to room temperature and passed through Celite^TMPad filtration, vacuumThe filtrate was concentrated to give an oil. Purification by silica gel column chromatography eluting with ether/petroleum ether as eluent gave the product as a yellow oil. This oil was dissolved in THF (2mL), then tetrabutylammonium fluoride (336.4 μ L, 1M, 0.3364mmol) was added and the resulting solution was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (5mL), washed with water and brine, and concentrated in vacuo to give a solid, which was dissolved in dichloromethane (10mL) and trifluoroacetic acid (19.18mg, 12.96. mu.L, 0.1682mmol) was added. The resulting mixture was stirred at room temperature for 1h, then concentrated in vacuo to give an oil which was purified by preparative HPLC [ Waters Sunfire C18, 10mM, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Freeze-drying the product fractions to give the product as a solid (12.0mg, 24% yield); 1H NMR (400.0MHz, MeOD) d 2.77(s, 1H), 6.42-6.5(m, 1H), 6.55-6.62(m, 1H), 6.6-6.75(m, 4H), 6.82(d, 1H), 7.3(d, 1H) and 7.83(s, 1H) ppm; MS (ES)⁺)340.1

Example 15A: 4- (5-amino-6- (5- (2-vinylphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (compound IA-77)

Synthetic route

Compound IA-77

Compounds I A-77 were prepared using method I V-B, step 1-2, then method IV-L, step 1, then method IV-O, step 1.

Process IV-O

Step 1: 4- (5-amino-6- (5- (2-vinylphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

To give 4- [ 5-amino-6- [5- (2-iodophenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]A solution of-N, N-dimethyl-benzamide (100mg, 0.1952 mmo), trifluoro-vinyl-potassium boron (31.37mg, 0.2342mmol), triethylamine (81.63 μ L, 0.5857mmol) and cyclopenta-1, 4-dien-1-yl (diphenyl) phosphine, dichloromethane, palladium dichloride, iron (31.88mg, 0.03904mmol) in propanol (2.000mL) was degassed, nitrogen (3 ×) was charged and the resulting solution was heated at 100 ℃ for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification was by silica gel column chromatography eluting with ethyl acetate. Product fractions were combined and concentrated in vacuo to give the product as a yellow solid (43.1mg, 53% yield); 1H NMR (400.0MHz, DMSO) d2.97(m, 6H), 5.51(m, 1H), 5.98(m, 1H), 7.54(m, 2H), 7.58-7.70(m, 3H), 7.78(br s, 2H), 7.89(m, 1H), 8.06(m, 2H) and 9.00(s, 1H) ppm; MS (ES) ⁺)413.15

Example 16A: 2- (5-amino-6- (5- (thiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -5- (1, 4-diazepan-1-carbonyl) benzonitrile (Compound IA-152)

Synthetic route

Compound IA-152

Compound IA-152 was prepared using method IV-P, step 1-2.

Process IV-P

Step 1: 5-bromo-3- (5- (thiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

3-amino-6-bromo-pyrazine-2-carboxylic acid (3.2g, 14.68mmol) and thiophene-2-carbohydrazide (2.152g, 14.68mmol) were suspended in acetonitrile (48.00mL) at room temperature, dibromo (triphenyl) phosphane (24.79g,58.72mmol) and then acetonitrile (16.00mL) was added. The reaction mixture turned bright yellow and was stirred at room temperature for 1 h. After this time, the reaction mixture was cooled in an ice bath, and DIPEA (7.209g, 9.716mL, 55.78mmol) was added dropwise. The reaction mixture was stirred in the ice bath for 1h, then DIPEA (2.277g, 3.069mL, 17.62mmol) was added, the reaction mixture was kept stirred for 30min, and DIPEA (1.897g, 2.557mL, 14.68mmol) was added. The reaction mixture was stirred for 1h and then filtered. The solid was washed with diethyl ether, isolated, then triturated with acetonitrile and washed with diethyl ether to give the product as a yellow solid (2.776g, 57% yield); 1HNMR (400.0MHz, DMSO)7.35(s, 1H), 7.80(br s, 2H), 7.98(m, 1H), 8.04(m, 1H) and 8.45(s, 1H); MS (ES) ⁺)326.04

Step 2: 2- (5-amino-6- (5- (thiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -5- (1, 4-diazepan-1-carbonyl) benzonitrile

Tert-butyl 4- (4-bromo-3-cyano-benzoyl) -1, 4-diazepan-1-carboxylate (126.0mg, 0.3085mmol), potassium acetate (90.83mg, 0.9255mmol), 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolan (117.5mg, 0.4628mmol) and 1-cyclopentyl-1, 4-dienyl-diphenyl-phosphine, dichloromethane, dichloropalladium, iron (25.19mg, 0.03085mmo l) were heated in dioxane (3mL) at 80 ℃ for 3 h. Sodium carbonate (462.8 μ L, 2M, 0.9255mmol) was added to the reaction mixture followed by tert-butyl 4- (4-bromo-3-cyano-benzoyl) -1, 4-diazepan-1-carboxylate (126.0mg, 0.3085mmol) and palladium, triphenylphosphine (35.65mg, 0.03085mmol), the reaction mixture was evacuated, flushed with nitrogen (3 cycles), and then heated in a microwave at 150 ℃ for 1 h.

The reaction mixture was diluted with water (10mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3X 10 mL). With MgSO₄The combined extracted organic layers were dried, filtered and evaporated to dryness to give a brown/black solid. The solid was redissolved in MeOH/DCM (4mL) and the solution was filtered through a thiol column to give a brown solid. It is ground with acetonitrile The product was obtained as a brown solid. The black solid was redissolved in DCM (3mL), TFA (500. mu.L, 6.490mmol) was added, and the resulting mixture was stirred at room temperature for 15 min. The solution was evaporated to dryness, then MeOH/DCM was added and the mixture was concentrated in vacuo. The solid was then redissolved in acetonitrile/water and passed through a bicarbonate column. The filtrate was then freeze-dried to give the product as a yellow solid (29.8mg, 20% yield); 1H NMR (400.0MHz, DMSO) d 1.60(br s, 1H), 1.75(br s, 1H), 2.70-2.80(m, 3H), 2.90(m, 1H), 3.35(m, 3H), 3.60-3.70(m, 2H), 7.30-7.40(m, 1H), 7.80-7.90(m, 2H), 7.95-8.15(m, 5H) and 8.89(s, 1H) ppm; MS (ES)⁺)473.26

All of the following compounds were prepared using procedures analogous to those described above for compound IA-152.

The compound IA-1795- (2-methylsulfinylphenyl) -3- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d2.7(s, 3H), 3.1(s, 3H), 7.2-7.25(m, 1H), 7.6-7.8(m, 3H), 7.9(s, 1H), 8.05(d, 1H), 8.25(d, 1H) and 8.95(s, 1H) ppm; MS (ES)⁺)398.1

Example 17A: 3- (5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) pyridine-4-carbonitrile (Compound IA-153)

Compound IA-153

Compound IA-153 was prepared using method IV-a, step 1-2, then using method IV-N, step 1, then using method IV-Q, step 1-2.

Method IV-Q

Step 1: di-tert-butyl 5- (4-cyanopyridin-3-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yliminodicarbonate

Reacting N- [ 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazole-2-yl) pyrazin-2-yl]-N-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (150mg, 0.2894mmo L), 3- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carbonitrile (75.03mg, 0.3473mmol), cesium fluoride (87.92mg, 0.5788mmol), copper iodide (5.512mg, 0.9790. mu.L, 0.02894mmol) and palladium, triphenylphosphine (16.72mg, 0.01447mmol) were placed in a microwave tube evacuated and filled with nitrogen (x 5). Dioxane (2.486mL) was added and the reaction mixture was stirred during 5 further vacuum/aeration cycles. The resulting solution was stirred at 85 ℃ overnight, cooled to room temperature and diluted with ethyl acetate. With NaHCO₃The mixture was washed with aqueous solution (1X 10mL) and brine (1X 10mL), MgSO₄Drying, and concentrating under reduced pressure. Purify the material by silica gel column chromatography, eluting with 50-60% ethyl acetate/petroleum ether, to give the product as a colorless foam (136mg, 86.8%); 1H NMR (400.0MHz, DMSO)1.34(s, 18H), 7.19(s, 2H), 7.49(m, 3H), 7.75(m, 1H), 8.17(m, 2H), 8.40(m, 1H), 8.90(m, 1H) and 9.12(s, 1H) ppm

Step 2: 3- (5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) pyridine-4-carbonitrile

N-tert-Butoxycarbonyl-N- [5- (4-cyano-3-pyridyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl in dichloromethane (2mL) was treated with TFA (2mL, 25.96mmol)]Tert-butyl carbamate (140mg, 0.2585mmol) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, redissolved in MeOH/DCM, concentrated (2 ×), dissolved in MeOH/DCM, passed through a bicarbonate column, and concentrated under reduced pressure to give a yellow solid. Triturate the solid with acetonitrile and filter to give a yellow solid (83mg, 94%); 1H NMR (400.0MHz, DMSO) d7.69-7.77(m, 3H), 8.07(d, 1H), 8.24-8.26(m, 2H), 7.80-8.40(brs, 2H), 8.90(d, 1H), 9.09(s, 1H) and 9.47(s, 1H) ppm; MS (ES)⁺)342.16

All of the following compounds were prepared using procedures analogous to those described above for compound IA-153.

The compound IA-743- [ 5-amino-6- (5-phenyl-1, 3, 4-Oxadiazol-2-yl) pyrazin-2-yl]Pyridine-2-carbonitrile 1H NMR (400.0MHz, DMSO) d 7.64-7.70(m, 3H), 7.86-7.89(m, 1H), 8.18-8.20(m, 2H), 8.54-8.57(m, 1H), 8.79-8.81(m, 1H) and 8.94(s, 1H) ppm; MS (ES)⁺)342.16

The compound IA-1322- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ]-5-isopropylsulfonyl-benzonitrile 1H NMR (400.0MHz, CDCl)₃) d1.35(d, 6H), 7.5-7.6(m, 4H), 8.0-8.05(m, 1H), 8.1-8.15(m, 1H), 8.2-8.25(m, 2H), 8.3-8.32(m, 1H) and 8.7(s, 1H) ppm; MS (ES)⁺)447.2

Example 18A: 4- (5-amino-6- (5- (3-nitrophenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (compound IA-286)

Synthetic route

Compound IA-286

Compound IA-286 was prepared using method IV-C, step 1-2, followed by method IV-R, step 1.

Process IV-R

Step 1: 4- (5-amino-6- (5- (3-nitrophenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

Dibromo (triphenyl) phosphane (707.8mg, 1.68mmol) was added to 3-amino-6- [4- (dimethylcarbamoyl) phenyl group at room temperature]Pyrazine-2-carboxylic acid (100mg, 0.35mmol) and 4- (5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide (63.28mg, 0.35mmol) in acetonitrile (5 mL). A bright yellow solution was observed. The reaction mixture was stirred at room temperature for 30 min. DIPEA (304. mu.L, 1.75mmol) was added dropwise and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and the solid was taken up with acetonitrileTrituration afforded the product as a yellow solid (78.5mg, 51.3% yield); 1H NMR (400.0MHz, DMSO) d 2.98(m, 6H), 7.56(m, 2H), 7.85(br s, 1H), 7.99(t, 1H), 8.17(m, 2H), 8.52(m, 1H), 8.56(m, 1H), 8.82(m, 1H) and 9.02(s, 1H) ppm; MS (ES) ⁺)432.2

All of the following compounds were prepared using procedures analogous to those described above for compound IA-286.

Compound IA-854- [ 5-amino-6- [5- (3-hydroxyphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 3.02(m, 6H), 7.11(m, 1H), 7.52(m, 1H), 7.59(m, 3H), 7.64(m, 1H), 7.84(br s, 2H), 8.22(m, 2H), 9.04(s, 1H) and 10.13(1H, s) ppm; MS (ES)⁺)402.23

The compound IA-1804- [ 5-amino-6- (5-thiazol-4-yl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d2.78(m, 6H), 7.35(m, 2H), 7.60(br s, 1H), 7.94(m, 2H), 8.62(m, 1H), 8.79(s, 1H) and 9.22(m, 1H) ppm; MS (ES)⁺)394.15

Compound IA-1873- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Benzonitrile 1H NMR (400.0MHz, DMSO) d 1.20(d, 6H), 3.47(q, 1H), 7.92(br s, 2H), 7.90(t, 1H), 7.99(m, 2H), 8.19(dt, 1H), 8.41 to 8.43(m, 2H), 8.48 to 8.51(m, 1H), 8.58(t, 1H) and 9.09(s, 1H) ppm; MS (ES)⁺)447.2

The compound IA-1894- [ 5-amino-6- [5- (3-cyano-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals ]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.97(m, 6H), 7.50(m, 2H), 7.80(m, 1H), 8.21(m, 3H) and 9.05(s, 1H) ppm; MS (ES)⁺)418.15

Compound IA-2154- [ 5-amino-6- [5- (2-hydroxyphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.97(s, 3H), 3.01(s, 3H), 7.09-7.14(m, 2H), 7.53-7.55(m, 3H), 7.80 (m: (1H))br s, 2H), 7.93(dd, 1H), 8.16(d, 2H), 8.99(s, 1H) and 10.45(s, 1H) ppm; MS (ES)⁺)403.23

The compound IA-2464- [ 5-amino-6- [5- (4-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.34(s, 3H), 2.98(m, 6H), 7.54(m, 2H), 7.62(s, 1H), 7.75(br s, 2H), 7.85(s, 1H), 8.15(m, 2H) and 8.98(s, 1H) ppm; MS (ES)⁺)407.18

The compound IA-2734- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Benzonitrile 1H NMR (400.0MHz, DMSO) d1.20(d, 6H), 3.48(m, 1H), 7.99(d, 2H), 7.80-8.30(br s, 2H), 8.15(d, 2H), 8.34(d, 2H), 8.40(d, 2H) and 9.09(s, 1H) ppm; MS (ES)⁺)447.19

Example 19A: 5- (2- (isopropylsulfinyl) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (compound IA-136)

Synthetic route

Compound IA-136

Compound IA-136 was prepared using method IV-a, steps 1-3, followed by method IV-S, step 1.

Method IV-S

Step 1: 5- (2- (isopropylsulfinyl) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

5- (2-Isopropylsulfanylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (50mg, 0.1284mmol) was dissolved in dichloromethane (10mL) and cooled to 0 ℃ with an ice bath. 3-Chloroperbenzoic acid (26.59mg, 0.1541mmol) was added in one portion with rapid stirring. Stirring the mixture at 0 deg.CStirring for 15min, adding saturated NaHCO₃Aqueous solution (1X5mL) and brine (1X5mL) were washed with MgSO 4₄Drying and vacuum concentration gave a solid which was purified by silica gel column chromatography eluting with ether/petroleum ether to give the product as a yellow solid (16.1mg, 31% yield); 1H NMR (400.0MHz, CDCl)₃) d1.2(d, 3H), 1.35(d, 3H), 3.5-3.6(m, 1H), 7.5-7.75(m, 2H), 7.5-7.65(m, 7H), 8.25(d, 2H) and 8.55(s, 1H) ppm; MS (ES)⁺)406.1

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-136.

The compound IA-2565- (2-ethylsulfinylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, CDCl) ₃) d 1.25-1.4(m, 3H), 3.3-3.6(m, 2H), 7.6-7.8(m, 6H), 8.2(d, 2H), 8.4(d, 1H) and 8.6(s, 1H) ppm; MS (ES)⁺)392.2

Example 20A: 5- (2-Isopropylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (Compound IA-121)

Synthetic route

Compounds IA-121

Compounds IA-121 were prepared using method IV-A, steps 1-3, followed by method IV-T, step 1.

Method IV-T

Step 1: 5- (2-isopropylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

5- (2-Isopropylsulfanylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (40mg, 0.1027mmol) is dissolved in dichloromethane (10mL) and 3-chloroperbenzene is added stepwise over a period of 10minFormic acid (70.89mg, 0.4108 mmol). The resulting mixture was stirred at room temperature for 2h and poured onto a 50/50 mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate (20 mL). The layers were separated and diluted NaHCO was used₃The organic layer was washed with solution (1 × 10mL) and brine (1 × 10mL) and then concentrated in vacuo to give a solid. The solid was purified by silica gel column chromatography, eluting with 50% diethyl ether/petroleum ether, to give the product as a yellow solid (20.25mg, 36% yield); 1H NMR (400.0MHz, CDCl) ₃) d 1.4(d, 6H), 4.48-4.52(m, 1H), 7.0(br s, 2H), 7.5-7.7(m, 5H), 7.7-7.75(m, 1H), 8.2(d, 1H), 8.3(d, 1H) and 8.55(s, 1H) ppm; MS (ES)⁺)422.2

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-121.

The compound IA-164N- [2- [2- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]Phenyl radical]Sulfinyl ethyl group]Carbamic acid tert-butyl ester 1H NMR (400.0MHz, CDCl)₃) d 1.55(s, 9H), 3.45-3.5(m, 1H), 3.6-3.7(m, 3H), 5.5(br s, 1H), 7.6-7.8(m, 6H), 8.2-8.25(m, 2H), 8.3(d, 1H) and 8.6(s, 1H) ppm; MS (ES)⁺)507.2

The compound IA-2035- (2-ethylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, CDCl)₃) d 1.2(d, 3H), 1.35(d, 3H), 3.5-3.6(m, 1H), 7.5-7.75(m, 2H), 7.5-7.65(m, 7H), 8.25(d, 2H) and 8.55(s, 1H) ppm; MS (ES)⁺)408.2

The compounds IA-2805- (4-tert-butylsulfonylphenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.32(s, 9H), 7.7-7.8(m, 3H), 7.9-8.0(m, 3H), 8.20-8.25(m, 2H), 8.45(d, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)436.2

Example 21A: 4- (5-amino-6- (5- (2-ethoxyphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (Compound IA-277)

Synthetic route

Compounds IA-277

Compound IA-277 was prepared using method I V-C, step 1-2, then using method IV-R, step 1, then using method IV-U, step 1.

Method IV-U:

step 1: 4- (5-amino-6- (5- (2-ethoxyphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

Potassium carbonate (25.46mg, 0.1842mmol) was added to 4- [ 5-amino-6- [5- (2-hydroxyphenyl) -1, 3, 4-oxadiazol-2-yl at room temperature]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide (50mg, 0.1228mmol) in DMF (1 mL). A color change from yellow to orange was observed. The resulting suspension was heated at 60-65 deg.C and ethyl bromide (14.72mg, 10.01. mu.L, 0.1351mmol) was added slowly. After the addition was complete, the reaction was heated at 60-65 ℃ for 30 min. The reaction mixture was cooled to room temperature. Water (2mL) was added slowly and the mixture was stirred at room temperature for 20 min. A precipitate formed, which was filtered and washed with water. Redissolve the solid in DCM and use MgSO₄Dried, filtered and evaporated to dryness. Trituration of the solid with acetonitrile afforded the product as a yellow solid (38.3mg, 73% yield); 1H NMR (400.0MHz, DMSO) d 1.49(t, 3H), 2.97-3.02(m, 6H), 4.24-4.29(m, 2H), 7.17-7.18(m, 1H), 7.20(d, 1H), 7.32-7.35(m, 2H), 7.53(d, 1H), 7.65(br s, 2H), 8.05(d, 1H), 8.17(d, 2H) and 8.99(s, 1H) ppm; MS (ES) ⁺)431.24

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-277.

The compound IA-1084- [ 5-amino-6- [5- (2-isopropoxyphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N，N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 1.40(d, 6H), 2.99(s, 3H), 3.01(s, 3H), 4.90(q, 1H), 7.20(t, 1H), 7.39(d, 1H), 7.51-7.53(m, 2H), 7.55-7.65(m, 1H), 7.80(brs, 2H), 8.05-8.10(m, 1H), 8.17-8.20(m, 2H) and 8.99(s, 1H) ppm; MS (ES)⁺)445.27

The compound IA-175N- [2- [2- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl]Pyrazin-2-yl radicals]-1, 3, 4-oxadiazol-2-yl]Phenoxy radical]Ethyl radical]Carbamic acid tert-butyl ester 1H NMR (400.0MHz, DMSO) d 1.29(s, 9H), 2.96(s, 3H), 3.00(s, 3H), 3.50(d, 2H), 4.18(s, 2H), 6.96-6.99(m, 1H), 7.19-7.25(m, 1H), 7.35(d, 1H), 7.53(d, 2H), 7.66-7.67(m, 1H), 7.80(br s, 2H), 8.06-8.08(m, 1H), 8.16(d, 2H) and 8.99(s, 1H) ppm; MS (ES)⁺)546.27

Compound IA-1964- [ 5-amino-6- [5- [2- (2-hydroxyethoxy) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1HNMR (400.0MHz, DMSO) d 2.98(s, 3H), 3.00(s, 3H), 3.86-3.89(m, 2H), 4.23(s, 2H), 4.85(t, 1H), 7.19-7.22(m, 1H), 7.35-7.37(m, 1H), 7.54(d, 2H), 7.63-7.67(m, 1H), 7.79(br s, 2H), 8.02-8.04(m, 1H), 8.18(s, 2H) and 8.99(s, 1H) ppm; MS (ES) ⁺)447.24

The compound IA-2844- [ 5-amino-6- [5- [2- (3-hydroxypropoxy) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1HNMR (400.0MHz, DMSO) d 2.00(s, 2H), 2.97(s, 3H), 3.01(s, 3H), 3.65(d, 2H), 4.26(s, 2H), 4.55(s, 1H), 7.19(s, 1H), 7.35(s, 1H), 7.54(d, 2H), 7.70(br s, 2H), 8.03(d, 1H), 8.16(d, 2H) and 8.98(s, 1H) ppm; MS (ES)⁺)461.26

Example 22A: 4- (5-amino-6- (5- (2-aminophenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (Compound IA-99)

Synthetic route

Compounds IA-99

Compound IA-99 was prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-V, step 1.

Methods IV-V

Step 1: 4- (5-amino-6- (5- (2-aminophenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

SnCl is added at room temperature₂.2H₂O (151.6mg, 0.6720mmol) was added to 4- [ 5-amino-6- [5- (2-nitrophenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide (58mg, 0.1344mmol) in EtOAc (3mL) and dichloromethane (1mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was carefully poured into saturated aqueous sodium bicarbonate (5mL) and the layers were separated. The aqueous layer was extracted with additional dichloromethane (2 × 15mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo to give a yellow solid. It was purified by reverse phase preparative HPLC [ waters sunfire C18, 10mM, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Product fractions were freeze-dried to give the product as a yellow solid (17.2mg, 34% yield); 1HNMR (400.0MHz, DMSO) d 2.98(m, 6H), 6.78(t, 1H), 6.88(br s, 1H), 7.34(m, 1H), 7.55(m, 2H), 7.79(br s, 2H), 7.85(m, 1H), 8.18(m, 2H) and 8.99(s, 1H) ppm; MS (ES)⁺)402.26

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-99.

Compound IA-1424- [ 5-amino-6- [5- (3-aminophenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N，N-Dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d 2.98(m, 6H), 6.88(m, 1H), 7.31(m, 2H), 7.41(m, 1H), 7.56(m, 2H), 7.78(br s, 2H), 8.15(m, 2H) and 8.98(s, 1H) ppm; MS (ES)⁺)402.19

Example 23A: 5- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (compound IA-200)

Synthetic route

Compound mm-200

Compound IA-200 was prepared using method IV-a, step 1-2, then using method IV-N, step 1, then using method IV-W, step 1-2.

Method IV-W

Step 1: di-tert-butyl (5- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) iminodicarbonate

Reacting N- [ 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazole-2-yl) pyrazin-2-yl]-N-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (100mg, 0.19mmol) dissolved in DMF (1mL) and 1-methyl-4- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine (70.19mg, 0.23mmol) and Pd (PPh)₃)₂Cl₂(13.54mg, 0.019 mmol). Adding K₂CO₃(289. mu.L, 0.58mmol, 2M aqueous solution), the reaction mixture was heated at 100 ℃ for 12 hours. The reaction mixture was cooled to room temperature and used in the next step without further purification.

Step 2: 5- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

Dilute with dichloromethane (5mL)Di-tert-butyl (5- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) iminodicarbonate (118.6mg, 0.19mmol) as a solution in DMF (1mL) was treated with TFA (1mL, 12.98 mmol). The resulting solution was stirred at room temperature for 18h, then concentrated in vacuo. The residue was purified by preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min ]. Fractions were collected, lyophilized to give the product as a yellow solid (27.3mg, 27% yield); 1H NMR (400.0MHz, DMSO) d 2.87(d, 3H), 3.08-3.21(m, 4H), 3.40-3.53(m, 2H), 4.52(d, 2H), 7.12(d, 1H), 7.66-7.70(m, 5H), 8.16-8.18(m, 2H), 8.33(dd, 1H), 8.92(s, 1H), 8.93(d, 1H) and 9.75(br s, 1H) ppm; MS (ES)⁺)415.2

All of the following compounds were prepared using procedures analogous to those described above for compound IA-200.

Compound IA-725- [6- (2-morpholinoethylamino) -3-pyridinyl]-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, CDCl)₃) d3.17(br s, 4H), 3.29(t, 2H), 3.92-3.94(m, 6H), 7.03(d, 1H), 7.51-7.58(m, 3H), 8.18-8.21(m, 2H), 8.38(d, 1H), 8.49(s, 1H) and 8.52(s, 1H) ppm; MS (ES)⁺)445.2

The compounds IA-865- (3-methoxy-4-pyridinyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 4.09(s, 3H), 7.66-7.72(m, 3H), 7.96(br s, 2H), 8.12(br d, 1H), 8.17(dd, 2H), 8.47(d, 1H), 8.64(s, 1H) and 9.03(s, 1H) ppm; MS (ES)⁺)347.1

The compounds IA-1175- (6-methoxy-3-pyridyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 3.93(s, 3H), 6.99(d, 1H), 7.67-7.73(m, 5H), 8.17-8.20(m, 2H), 8.42(dd, 1H), 8.93(d, 1H) and 8.95(s, 1H) pp m；MS(ES⁺)347.1

Compound IA-1655- [2- (2-dimethylaminoethyloxy) -4-pyridinyl]-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 2.23(s, 6H), 2.65(t, 2H), 4.41(t, 2H), 7.49(s, 1H), 7.69-7.73(m, 4H), 7.95(br s, 2H), 8.16-8.19(m, 2H), 8.28(d, 1H) and 9.07(s, 1H) ppm; MS (ES)⁺)404.1

The compounds IA-1863- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -5- (6-piperazin-1-yl-3-pyridyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 3.00(br d, 4H), 3.58(br t, 4H), 6.86(d, 1H), 7.42-7.48(m, 5H), 7.94(dd, 2H), 8.09(dd, 1H), 8.53(br s, 2H), 8.68(s, 1H) and 8.69(d, 1H) ppm

The compound IA-265N' - [4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]-2-pyridyl]-N, N-dimethyl-ethane-1, 2-diamine 1H NMR (400.0MHz, DMSO) d 2.20(s, 6H), 2.45(t, 2H), 3.41(q, 2H), 6.54(t, 1H), 7.18(dd, 1H), 7.21(s, 1H), 7.67-7.74(m, 3H), 7.86(br s, 2H), 8.08(d, 1H), 8.18(dd, 2H) and 8.89(s, 1H) ppm; MS (ES)⁺)403.2

The compound IA-2795- [6- [3- (dimethylamino) propoxy-]3-pyridyl group]-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.89(qu i n, 2H), 2.16(s, 6H), 2.36(t, 2H), 4.35(t, 2H), 6.96(d, 1H), 7.68-7.71(m, 5H), 8.17-8.19(m, 2H), 8.40(dd, 1H), 8.91(d, 1H) and 8.94(s, 1H) ppm; MS (ES) ⁺)418.2

The compounds IA-2835- (6-morpholino-3-pyridinyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 3.33-3.35(m, 4H), 3.52-3.54(m, 4H), 6.79(d, 1H), 7.42-7.51(m, 5H), 7.95-7.97(m, 2H), 8.07(dd, 1H) and 8.69(s, 2H) ppm; MS (ES)⁺)402.1

Example 24A: 5- (2- (2-Aminoethylthio) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (compound IA-224)

Synthetic route

Compound IA-224

Compound IA-224 was prepared using method IV-a, steps 1-3, followed by method IV-Q, step 2.

Compounds IA-2245- (2- (2-aminoethylthio) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d2.9-3.0(m, 2H), 3.2(t, 2H), 7.8(t, 1H), 7.95(t, 1H), 7.6-7.75(m, 5H), 7.75-7.85(br s, 3H), 8.15(d, 2H) and 8.55(s, 1H) ppm; MS (ES)⁺)391.2

Example 25A: 5- (2- (2-Aminoethylsulfinyl) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (compound IA-261)

Compound mm-261

Compounds IA-261 were prepared using method IV-a, steps 1-3, then using method IV-S, step 1, then using method IV-Q, step 2.

Compound IA-2615- (2- (2-aminoethylsulfinyl) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d2.9-3.0(m, 1H), 3.1-3.2(m, 1H), 3.3-3.4(m, 1H), 3.55-3.62(m, 1H), 7.6-7.75(m, 8H), 7.8-7.9(m, 2H), 8.2-8.3(m, 4H) and 8.55(s, 1H) ppm; MS (ES) ⁺)407.2

Example 26A: 4- [ 5-amino-6- [5- (6-amino-2-pyridinyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-231)

Synthetic route

Compound IA-231

Compound IA-231 was prepared using method IV-C, step 1-2, followed by method IV-X, step 1-2.

Process IV-X

Step 1: 4- (5-amino-6- (2- (6-aminopyridine-2-carbonyl) hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide

A solution of 4- [ 5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl ] -N, N-dimethyl-benzamide (100mg, 0.3163mmol) and 6-aminopyridine-2-carboxylic acid (43.69mg, 0.3163mmol) in DMF (1.000mL) was treated with triethylamine (32.01mg, 44.09 μ L, 0.3163mmol) and then warmed slowly. The mixture was cooled to room temperature and then treated with tetrafluoroboric acid (benzotriazol-1-yloxy-dimethylamino-methylene) -dimethyl-ammonium (121.9mg, 0.3796mmol) and stirred at room temperature overnight. The mixture was poured dropwise onto water (5ml) with rapid stirring, stirred at room temperature for 1h, then filtered to give a wet paste, which was dried under high vacuum at 100 ℃ overnight. It was used in the next step without purification.

Step 2: 4- [ 5-amino-6- [5- (6-amino-2-pyridinyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

To 4- [ 5-amino-6- [ [ (6-aminopyridine-2-carbonyl) amino ] cooled in an ice bath]Carbamoyl radical]Pyrazin-2-yl radicals]To a suspension of-N, N-dimethyl-benzamide (80mg, 0.1903mmol) in dry acetonitrile (1.600mL) was added DIPEA (73.78mg, 99.43. mu.L, 0.5709mmol) followed by stepwise addition of dibromo (triphenyl) phosphane (104.4mg, 0.2474 mmol). Will obtainThe mixture was stirred at room temperature for 30 min. The precipitate was isolated by filtration and washed with a small amount of acetonitrile to give a pale yellow solid. The solid was triturated hot in acetonitrile, frozen, filtered, washed with acetonitrile then ether to give the pure product (36.1mg, 54% yield); 1HNMR (400MHz, DMSO) d 2.98-3.02(m, 6H), 6.53(br s, 2H), 6.69(m, 1.5H), 7.16(m, 0.5H), 7.16(m, 1H), 7.53-7.66(m, 3H), 8.11(m, 2H) and 8.94(s, 1H) ppm; MS (ES)⁺)403.29

All of the following compounds were prepared using procedures analogous to those described above for compound IA-231.

Compounds IA-73N- [ [3- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl ] methyl ester]Pyrazin-2-yl radicals]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methyl radical]Carbamic acid tert-butyl ester 1H NMR (400.0MHz, DMSO) d 1.41(s, 9H), 2.98(m, 6H), 4.27(m, 2H), 7.54-7.60(m, 4H), 7.65(m, 1H), 7.79(br s, 2H), 8.03-8.05(m, 2H), 8.16(m, 2H) and 8.99(s, 1H) ppm; MS (ES) ⁺)516.3

Compound IA-954- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]-methyl 3, 6-dihydro-2H-pyridine-1-carboxylate 1HNMR (400MHz, DMSO) d 1.19(d, 6H), 1.45(s, 9H), 2.64(s, 2H), 3.39-3.53(m, 1H), 3.60(s, 2H), 4.18(s, 2H), 7.01(s, 1H), 7.85(s, 2H), 7.95(d, 2H), 8.36(d, 2H) and 9.05(s, 1H) ppm; MS (ES)⁺)527.3

Compound IA-1435- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Thiophene-3-carbonitrile 1H NMR (400MHz, DMSO) d1.20(d, 6H), 3.47(t, 1H), 7.97(d, 2H), 8.40(dd, 2H), 8.46(d, 1H), 8.97(d, 1H), and 9.08(s, 1H) ppm; MS (ES)⁺)453.0

Compound I A-154N- [1- [3- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Ethyl radical]Carbamic acid tert-butyl ester 1HNMR (400MHz, DMSO) d 1.19(m, 6H), 1.38(m, 12H), 3.48(m, 1H), 4.77(m, 1H), 7.64(m, 3H), 7.97(m, 2H), 8.03(m, 1H), 8.10(s, 1H), 8.39(m,2H) and 9.07(s, 1H) ppm; MS (ES)⁺)565.35

Compounds IA-162N- [ [4- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl ] methyl ] carbonyl]Pyrazin-2-yl radicals]-1, 3, 4-oxadiazol-2-yl]Phenyl radical ]Methyl radical]Carbamic acid tert-butyl ester 1H NMR (400.0MHz, DMSO) d 1.42(s, 9H), 2.98-3.02(m, 6H), 4.25(d, 2H), 7.51-7.56(m, 5H), 7.79(br s, 2H), 8.12-8.19(m, 4H) and 8.98(s, 1H) ppm; MS (ES)⁺)516.24

The compound IA-2234- [ 5-amino-6- [5- (2-amino-4-pyridinyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400MHz, DMSO) d 2.98-3.02(m, 6H), 6.49(br s, 2H), 7.13-7.17(m, 2H), 7.54-7.56(m, 2H), 7.80(br s, 2H), 8.14-8.19(m, 3H) and 9.00(1H, s) ppm; MS (ES)⁺)403.21

Compound IA-251N- [2- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Ethyl radical]Carbamic acid tert-butyl ester 1H NMR (400MHz, DMSO) d 1.19(d, 6H), 1.32(s, 9H), 2.08(s, 2H), 3.13(s, 2H), 3.31(d, 2H), 3.40(d, 1H), 7.05-7.08(m, 1H), 7.96(d, 2H), 8.32(d, 2H) and 9.02(s, 1H) ppm; MS (ES)⁺)489.27

Example 27A: 4- (5-amino-6- (5- (2-ethylphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (Compound IA-155)

Synthetic route

Compound IA-155

Compound IA-155 was prepared using method IV-B, step 1-2, then using method IV-L, step 1, then using method IV-O, step 1, then using method IV-Y, step 1.

Process IV-Y

Step 1: 4- (5-amino-6- (5- (2-ethylphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

4- [ 5-amino-6- [5- (2-vinylphenyl) -1, 3, 4-oxadiazol-2-yl ] is reacted using a parr apparatus]Pyrazin-2-yl radicals]A suspension of-N, N-dimethyl-benzamide (45mg, 0.1091mmol) in a mixture of ethanol (5mL) and acetic acid (0.5mL) was hydrogenated in the presence of Pd/C wet Degussa (116.1mg, 0.1091mmol) at 60ps i overnight. The reaction mixture was filtered through a pad of celite, which was washed with ethanol (5mL) and ethyl acetate (5 mL). With MgSO₄The filtrate was dried, filtered and concentrated in vacuo. Purification by preparative HPLC [ Waters Sunfire C18, 10mM,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]Product fractions were combined and lyophilized to give the product as a yellow solid (14.2mg, 38% yield); 1H NMR (400MHz, DMSO) d 1.30(t, 3H), 2.98(m, 6H), 3.13(q, 2H), 7.48-7.55(m, 4H), 7.62(m, 1H), 7.78(br s, 2H), 8.05(m, 1H), 8.14(m, 2H) and 8.99(1H, s) ppm; MS (ES)⁺)415.27

Example 28A: 4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] -N, N-dimethyl-3-prop-1-ynyl-benzamide (compound IA-268)

Compound IA-268

Compounds I A-268 were prepared using method IV-a, step 1-2, then using method IV-N, step 1, then using method IV-Z, step 1-2.

Process IV-Z

Step 1: di-tert-butyl (5- (4- (dimethylcarbamoyl) -2- (prop-1-ynyl) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) iminodicarbonate

With N- [ 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl]-N-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (77.91mg, 0.1503mmol), sodium carbonate (75.15. mu.L, 2M, 0.1503mmol) and palladium dichloride, triphenylphosphine (10.55mg, 0.01503mmol) and DMF (1.122mL) 4- (dimethylcarbamoyl) -2- (prop-1-ynyl) phenylboronic acid (52mg, 0.225mmol) and the resulting mixture was heated in a microwave at 95 ℃ for 1 h. The reaction mixture was diluted with EtOAc and NaHCO₃Aqueous NaCl (3 × 5mL) washed, dried over MgSO4, and concentrated in vacuo. Purification was by silica gel column chromatography eluting with 30-100% EtOAc in petroleum ether. The product fractions were combined and concentrated in vacuo to give a brown oil which was used directly in the next step.

Step 2: 4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] -N, N-dimethyl-3-prop-1-ynyl-benzamide

Treatment with TFA (200. mu.L, 2.596mmol) in CH₂Cl₂Di-tert-butyl (5- (4- (dimethylcarbamoyl) -2- (prop-1-ynyl) phenyl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) iminodicarbonate (200. mu.L) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and then passed through a bicarbonate column eluting with DCM/MeOH. The product was purified by silica gel column chromatography using 20-100% EtOAc/CH₂Cl₂Elution gave the product (2.6mg, 34% yield); 1H NMR (400MHz, CDCl)₃) d 1.97(s, 3H), 2.98-3.07(m, 6H), 7.40-7.52(m, 5H), 7.82(m, 1H), 8.19(m, 2H) and 8.90(s, 1H) ppm; MS (ES)⁺)425.21

Example 29A: 4- [ 5-amino-6- [5- [3- (aminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-183)

Compound IA-183

Compound IA-183 was prepared using method I V-B, steps 1-4, followed by method IV-AA, step 1.

Method IV-AA

Step 1: 4- [ 5-amino-6- [5- [3- (aminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

TFA (131.1mg, 88.58. mu.L, 1.150mmol) was added to N- [ [3- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl ] carbonyl ]Pyrazin-2-yl radicals]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methyl radical]To a solution of tert-butyl carbamate (60mg, 0.1150mmol) in dichloromethane (2mL) was stirred at room temperature overnight. The reaction mixture was passed through a bicarbonate column and charged with methanol (5 mL). The filtrate was concentrated in vacuo to give a yellow/orange solid. The solid was dissolved in a mixture of methanol and dichloromethane and passed through an SCX column. The column was initially washed with methanol and the product was then eluted in 4 sub-fractions with 2M ammonia in methanol. The yellow solid crystallized from the filtrate and was isolated by filtration to give the product (44mg, 90% yield) 1H NMR (400MHz, DMSO) d 2.98(m, 6H), 3.87(s, 2H), 7.55(m, 2H), 7.59-7.66(m, 2H), 7.81(br s, 2H), 8.00(m, 1H), 8.17(m, 3H) and 8.99(s, 1H) ppm; MS (ES)⁺)416.26

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-183.

Compound IA-2344- [ 5-amino-6- [5- [4- (aminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1H NMR (400MHz, DMSO) d 2.99-3.02(m, 6H), 4.20(s, 2H), 7.56(d, 2H), 7.75(d, 2H), 7.80(br s, 2H), 8.18(d, 2H), 8.23(d, 2H), 8.34(br s, 2H) and 9.00(s, 1H) ppm; MS (ES) ⁺)416.25

Example 30A: 4- [ 5-amino-6- [5- [2- (2-aminoethoxy) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-213)

Synthetic route

Compound IA-213

Compound IA-213 was prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AB, step 1.

Method IV-AB

Step 1: 4- [ 5-amino-6- [5- [2- (2-aminoethoxy) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

4- [ 5-amino-6- [5- (2-hydroxyphenyl) -1, 3, 4-oxadiazole-2-yl]Pyrazin-2-yl radicals]A mixture of-N, N-dimethyl-benzamide (50mg, 0.1228mmol) in DMF (1.000mL) was stirred at room temperature and potassium carbonate (25.46mg, 0.1842mmol) was added. The resulting suspension was heated at 60-65 deg.C and tert-butyl N- (2-bromoethyl) carbamate (30.28mg, 0.1351mmol) was added slowly. After the addition was complete, the reaction mixture was heated at 65 ℃ overnight. The reaction mixture was cooled to room temperature, water (2mL) was slowly added, and the mixture was stirred at room temperature for 20 min. A precipitate formed, which was isolated by filtration and washed with water (3 × 5 mL). Redissolving the solid in CH₂Cl₂Dried (MgSO)₄) Filtered and evaporated to dryness. The solid was triturated with DCM/ether and filtered to give a yellow solid. Yellow solid in CH ₂Cl₂To (1mL) was added TFA (150. mu.L, 1.947mmol) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH/CH₂Cl₂The mixture (4mL) was passed through a bicarbonate column eluting with MeOH/DCM. Evaporating the filtrate to drynessThen triturated with acetonitrile to give the product as a yellow solid (36.7mg, 69% yield) 1H NMR (400MHz, DMSO) d 2.98(s, 3H), 3.02(s, 3H), 3.31(t, 2H), 4.41(t, 2H), 7.30(t, 1H), 7.40(d, 1H), 7.56(d, 2H), 7.69-7.71(m, 2H), 7.87(s, 3H), 8.04(dd, 1H), 8.16(d, 2H) and 9.01(s, 1H) ppm; MS (ES)⁺)446.28

Example 31A: 4- (5-amino-6- (5- (3-methoxythiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide (Compound IA-172)

Synthetic route

Compounds IA-172

Compound IA-172 was prepared using method IV-C, step 1-2, followed by method IV-AC, step 1.

Method IV-AC

Step 1: 4- (5-amino-6- (5- (3-methoxythiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -N, N-dimethylbenzamide

TBTU (160.4mg, 0.4995mmol) and Et₃N (33.70mg, 46.42. mu.L, 0.3330mmol) was added to 4- (5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide (100mg, 0.3330mmol) and 3-methoxythiophene-2-carboxylic acid (52.67mg, 0.3330mmol) in CH ₂Cl₂(2.000mL), the resulting solution was stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane (5mL) and water (5mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (3X 5mL) and MgSO₄The combined organic extracts were dried, filtered, and concentrated in vacuo to give 4- [ 5-amino-6- [ [ (3-methoxythiophene-2-carbonyl) amino ] carbonyl]Carbamoyl radical]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide as a yellow oil. Adding POCl₃(1.788g1.087mL, 11.66mmol) was added to 4- [ 5-amino-6- [ [ (3-methoxythiophene-2-carbonyl) amino group]Carbamoyl radical]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide, and heating the resulting mixture at 100 ℃ for 2 h. The reaction mixture was cooled to room temperature and ice/water was carefully added with vigorous stirring between additions. The mixture was stirred at room temperature for 20min, then diluted with dichloromethane (10mL) and the layers separated. The aqueous layer was extracted with dichloromethane (2X 5mL) and MgSO₄The combined organic layers were dried and concentrated in vacuo. Redissolving the resulting solid in CH₂Cl₂Purified by column chromatography using an ISCO column company system (12g column, 0-5% MeOH/CH)₂Cl₂). The product fractions were combined and concentrated in vacuo. Further purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10mM, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Product fractions were combined, lyophilized to give the product as a yellow solid (33.0mg, 23% yield) 1H NMR (400MHz, DMSO) d 2.98(s, 3H), 3.01(s, 3H), 4.07(s, 3H), 7.30(d, 1H), 7.56(d, 2H), 7.70(br s, 2H), 7.96(d, 1H), 8.14(d, 2H) and 8.97(s, 1H) ppm; MS (ES)⁺)423.19

Example 31A: 2- (5-amino-6- (5- (3-methylthiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -5- (1, 4-diazepan-1-carbonyl) benzonitrile (Compound IA-181)

Synthetic route

Compound IA-181

Compound IA-181 was prepared using method IV-AD steps 1-5.

Method IV-AD

Step 1: 3-amino-6-bromo-N' - (3-methylthiophene-2-carbonyl) pyrazine-2-carboxylic acid hydrazide

To a suspension of 3-amino-6-bromo-pyrazine-2-carboxylic acid (13.26g, 60.82mmol) and 3-methylthiophene-2-carbohydrazide (10g, 60.82mmol) in DMF (95.00mL) cooled with an ice bath was added Et₃N (7.385g, 10.17mL, 72.98mmol) was then added gradually TBTU (23.43g, 72.98mmol) after the addition was complete and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (50mL) and water (50 mL). The layers were separated and the organic extract was washed with water (1X 50mL) and brine (1X 50mL) over MgSO ₄Dried and concentrated to give a brown solid (7.85g, 36% yield), which was used in the next step without further purification.

Step 2: 5-bromo-3- (5- (3-methylthiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

To a suspension of 3-amino-6-bromo-N' - (3-methylthiophene-2-carbonyl) pyrazine-2-carboxylic acid hydrazide (7.85g, 22.04mmol) in anhydrous acetonitrile (117.8mL) cooled with an ice bath was added DIPEA (8.546g, 11.52mL, 66.12mmol) followed by stepwise addition of dibromo (triphenyl) phosphane (12.09g, 28.65 mmol). The resulting suspension was stirred at room temperature for 30min, the precipitate was isolated by filtration and washed with acetonitrile to give the product as a yellow solid (4.42g, 52% yield); 1H NMR (400MHz, DMSO) d 2.64(s, 3H), 7.21(d, 1H), 7.91(3H, m) and 8.44(s, 1H) ppm; MS (ES)⁺)340.04

And step 3: tert-butyl-5-bromo-3- (5- (3-methylthiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl (tert-butoxycarbonyl) carbamate

Reacting 5-bromo-3- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazole-2-yl]Pyrazin-2-amine (10.68g, 31.58mmol) and DMAP (385.8mg, 3.158mmol) were suspended in CH₂Cl₂(160.2mL) and THF (160.2mL) were cooled with an ice bath. Tert-butyl tert-butoxycarbonyl carbonate (20.68g, 94.74mmol) was gradually added to the stirred mixture. The reaction mixture was stirred at room temperature Stirring for 1h, and then adding CH₂Cl₂(100ml) and saturated aqueous sodium bicarbonate solution (100 ml). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (2X 100ml) and MgSO₄Drying, filtering and vacuum concentrating. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether to give the product as a brown crystalline material (14.29g, 84% yield); 1H NMR (400MHz, DMSO) d 1.41(s, 9H), 2.72(s, 3H), 7.10(m, 1H), 7.55(m, 1H) and 8.74(s, 1H) ppm

And 4, step 4: 4- (4- (5- (bis (tert-butoxycarbonyl) amino) -6- (5- (3-methylthiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) -3-cyanophenylcarbonyl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

Reacting N- [ 5-bromo-3- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazole-2-yl]Pyrazin-2-yl radicals]-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (13.52g, 25.12mmol) and 4- [ 3-cyano-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]-1, 4-diazepan-1-carboxylic acid tert-butyl ester (11.44g, 25.12mmol) in DMF (160mL) and Na₂CO₃(37.68mL, 2M, 75.36mmol) (4: 1 mixture), the reaction mixture was degassed with nitrogen and Pd (tBu) was added in one portion₃P)₂(1.027g, 2.010 mmol). The resulting mixture was heated at 75 ℃ for 2.5 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (50mL) and water (50 mL). The organic extracts were washed with water (1X 100mL) and brine (1X 100mL), then the aqueous layer was back-extracted with ethyl acetate (3X 100mL), MgSO ₄Drying, filtering and vacuum concentrating. The material was passed through a pad of silica gel eluting with 50-100% EtOAc in petroleum ether. The material was purified by silica gel column chromatography (500mL) eluting with 30-100% EtOAc/petroleum ether. The product fractions were combined and concentrated in vacuo to give the product as a yellow solid (11.9g, 55% yield)

And 5: 2- [ 5-amino-6- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -5- (1, 4-diazepan-1-carbonyl) benzonitrile

4- [4- [5- [ bis (tert-butyloxycarbonyl) amino group at room temperature]-6- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-3-cyano-benzoyl]-1, 4-diazepan-1-carboxylic acid tert-butyl ester (9.9g, 11.32mmol) in anhydrous CH₂Cl₂(100mL), TFA (10mL, 129.8mmol) was added. TFA (10mL, 129.8mmol) was added further and the reaction mixture was stirred at room temperature for 3.5h, then concentrated in vacuo. This material was dissolved in a mixture of acetonitrile and methanol (10; 1 mixture) and PS-HCO was added₃(5 eq). The mixture was stirred at room temperature for 1h, then the resin was removed by filtration, washed with acetonitrile and methanol. The filtrate was concentrated in vacuo and the residue was recrystallized from acetonitrile. The isolated solid was washed with diethyl ether and dried to give the product as a yellow solid (2.41g, 35% yield); 1H NMR (400MHz, DMSO) d 1.76-1.84(m, 2H), 2.67(s, 3H), 2.88-2.93(m, 4H), 3.42-3.44(m, 2H), 3.67-3.74(m, 2H), 7.2(d, 1H), 7.84-7.87(m, 1H), 7.89-7.99(m, 1H), 8.04-8.09(m, 2H) and 8.85(s, 1H) ppm; MS (ES) ⁺)487.26

Example 32A: 1- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] pyrrole-2-carbonitrile (Compound IA-264)

Synthetic route

Compound IA-264

Compound IA-264 was prepared using method IV-a, step 1-2, then using method IV-N, step 1, then using method IV-AE, step 1.

Method IV-AE

Step 1: 1- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] pyrrole-2-carbonitrile

Reacting N- [ 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazole-2-yl) pyrazin-2-yl]-Boc-carbamic acid tert-butyl ester (100mg, 0.1929mmol) and carbonic acidCesium (125.7mg, 0.3858mmol) was added to DMF (5mL) followed by 1H-pyrrole-2-carbonitrile (26.65mg, 0.2894 mmol). The resulting mixture was heated at 50 ℃ for 1 h. The mixture was cooled to room temperature, filtered and diluted with ethyl acetate (5 mL). The organic layer was washed with water (1 × 10mL) and brine (1 × 10mL) and concentrated in vacuo to give an oil. Dissolving it in CH₂Cl₂(10mL), TFA (659.9mg, 445.9. mu.L, 5.787mmol) was added. The reaction mixture was stirred at room temperature for 1h, then concentrated in vacuo to give an oil. The oil was dissolved in CH₂Cl₂The product was precipitated by slow addition of petroleum ether (28.3mg, 45% yield); 1H NMR (400MHz, DMSO) d 6.6(s, 1H), 7.3(s, 1H), 7.7-7.85(m, 3H), 7.9(br s, 2H), 7.95(s, 1H), 8.2-8.25(m, 2H) and 8.8(s, 1H) ppm; MS (ES) ⁺)330.2

Example 33A: 4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] -2- (2-dimethylaminoethylamino) pyridine-3-carbonitrile (Compound IA-209)

Synthetic route

Compound IA-209

Compound IA-209 was prepared using method IV-a, step 1-2, then using method IV-N, step 1, then using method IV-Q, step 1, then using method IV-AF, step 1.

Method IV-AF

Step 1: 4- [ 5-amino-6- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl ] -2- (2-dimethylaminoethylamino) pyridine-3-carbonitrile

N, N-Dimethylethyl-1, 2-diamine (22.04mg, 27.45. mu.L, 0.2500mmol) was added to di-tert-butyl 5- (2-chloro-3-cyanopyridin-4-yl) -3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-yliminodicarbonateButyl ester (36mg, 0.06250mmol) and Et₃N (25.30mg, 34.85. mu.L, 0.2500mmol) in NMP (1mL) was heated at 150 ℃ for 2 hours under microwave conditions. This material was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH 3CN) over 16 min, 25mL/min]. Fractions were collected and lyophilized to give the title compound as a yellow solid (7.6mg, 24% yield); 1HNMR (400MHz, DMSO) d 2.88(d, 6H), 3.38(br m, 2H), 3.81-3.83(m, 2H), 7.34(d, 1H), 7.63-7.71(m, 3H), 8.22-8.24(m, 2H), 8.38(d, 1H), 8.96(s, 1H) and 9.23(br s, 1H) ppm; MS (ES) ⁺)428.3

Example 34A: 4- [ 5-amino-6- [5- [3- (hydroxymethyl) phenyl ] -1, 3, 4-oxadiazol μ -2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-198)

Synthetic route

Compound IA-198

Compounds IA-198 were prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AG, step 1.

Method IV-AG:

step 1: 4- [ 5-amino-6- [5- [3- (hydroxymethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

To diisobutylaluminum hydride (810.0. mu.L, 1M, 0.8100mmol) in dichloromethane was added dropwise 3- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl group at 0 deg.C]Pyrazin-2-yl radicals]-1, 3, 4-oxadiazol-2-yl]Benzoic acid AEster (120mg, 0.2700mmol) in CH₂Cl₂(6mL) which turned dark upon addition. The resulting solution was stirred at 0 ℃ for 30min, which was slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 4h, then quenched by addition of 1M HCl (3 mL). The resulting mixture was filtered through a pad of celite, washing with dichloromethane (2 × 5 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2X 10mL) and MgSO₄The combined organic extracts were dried and concentrated in vacuo. The residue was purified by using reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, 25mL/min]. Product fractions were combined and lyophilized to give the product as a yellow solid (20.3mg, 18% yield); 1HNMR (400MHz, DMSO) d 2.98(m, 6H), 4.66(s, 2H), 7.55(m, 2H), 7.63(m, 2H), 7.80(br s, 2H), 8.04(m, 1H), 8.16(m, 3H) and 8.99(s, 1H) ppm; MS (ES)⁺)417.23

Example 35A: 4- [ 5-amino-6- [5- [3- (2-hydroxyethyl) phenyl 1] -, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-69)

Synthetic route

Compound IA-69

Compound IA-69 was prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AH, step 1.

Method IV-AH

Step 1: 4- [ 5-amino-6- [5- [3- (2-hydroxyethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

To 4- [ 5-amino-6- [5- (3-vinylphenyl) -1, 3, 4-oxadiazol-2-yl at 0 DEG C]Pyrazin-2-yl radicals]A solution of-N, N-dimethyl-benzamide (100mg, 0.2425mmol) in THF (9.172mL) was added dropwise borane-THF complex (606.3. mu.L, 1M, 0.6063mmol) and the reaction mixture was stirred at room temperature overnight. Water (43.69mg, 43.69. mu.L, 2.425mmol) was added to the reaction mixture, then hydrogen peroxide (299.9. mu.L, 27.5% w/v, 2.425mmol) and NaOH (606.5. mu.L, 2M, 1.213mmol) were added and the mixture was stirred vigorously for 1 h. The mixture was partitioned between ethyl acetate (5mL) and water (5mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2X 5mL) and MgSO ₄The combined organic extracts were dried and concentrated in vacuo. The residue was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, 25mL/min]. Product fractions were combined and lyophilized to give the product as a yellow solid (5.8mg, 11% yield); 1H NMR (400MHz, DMSO) d 2.89(t, 2H), 2.98(m, 6H), 3.70(q, 2H), 4.75(t, 1H), 7.55-7.62(m, 4H), 7.80(br s, 2H), 8.01(m, 2H), 8.17(m, 2H) and 8.99(s, 1H) ppm; MS (ES)⁺)431.24

All of the following compounds were prepared using a procedure analogous to that described above for compounds I A-69.

Compound I A-2754- [ 5-amino-6- [5- [3- (1-hydroxyethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide 1HNMR (400MHz, DMSO) d 1.40(d, 3H), 2.98(m, 6H), 4.88(m, 1H), 5.46(m, 1H), 7.55(m, 2H), 7.62(m, 2H), 7.81(br s, 2H), 8.03(m, 1H), 8.16(m, 3H) and 8.99(s, 1H) ppm; MS (ES)⁺)431.24

Example 36A: 4- [ 5-amino-6- [5- [2- (3-thienyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-127)

Synthetic route

Compounds IA-127

Compounds IA-127 were prepared using method IV-B, step 1-2, then method IV-L, step 1, then method IV-AI, step 1.

Process IV-AI

Step 1: 4- [ 5-amino-6- [5- [2- (3-thienyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

Reacting 4- [ 5-amino-6- [5- (2-bromophenyl) -1, 3, 4-oxadiazole-2-yl]Pyrazin-2-yl radicals]A solution of-N, N-dimethyl-benzamide (50mg, 0.108mmol), thiophen-3-ylboronic acid (13.8mg, 0.108mmol), cesium carbonate (107 μ Ι _ of 2M aqueous solution) and palladium dichloride, triphenylphosphine (7.55mg, 0.0108mmol) in dioxane (2mL) was heated at 110 ℃ for 1h in a microwave. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by preparative HPLC [ Waters sunfire c18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH 3CN) over 16 min, 25mL/min]. Product fractions were combined and lyophilized to give the product as a yellow solid (7.4mg, 17% yield); 1H NMR (400MHz, DMSO) d 2.97(m, 6H), 7.09(m, 1H), 7.53(m, 2H), 7.60(m, 2H), 7.64(m, 2H), 7.71-7.76(m, 3H), 8.01(m, 2H), 8.07(m, 1H) and 8.95(s, 1H) ppm; MS (ES) ⁺)469.22

Example 37A: 3- [5- [3- (aminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound IA-220)

Synthetic route

Compounds IA-220

Compound IA-220 was prepared using method IV-AJ, steps 1-4.

Process IV-AJ

Step 1: 3-amino-6-bromopyrazine-2-carboxylic acid hydrazides

3-amino-6-bromo-pyrazine-2-carboxylic acid methyl ester (10.18g, 43.87mmol) was suspended in EtOH (50.90mL), hydrazine hydrate (4.392g, 4.268mL, 87.74mmol) was added and the reaction mixture was heated at 70 ℃ for 2 h. Water (50mL) was added and the precipitate was isolated by filtration. The solid was washed with methanol and dried in vacuo to give the product as a pale yellow powder (9.8g, 96% yield); 1H NMR (400MHz, DMSO) d 4.53(bs s, 2H), 7.62(br s, 2H) and 9.78(br s, 1H) ppm; MS (ES)⁺)232.06

Step 2: 3- (5- (3-amino-6-bromopyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) benzylcarbamic acid tert-butyl ester

3-amino-6-bromo-pyrazine-2-carboxylic acid hydrazide (1.2g, 5.172mmol), TBTU (1.333g, 5.689mmol) and 3- [ (tert-butoxycarbonylamino) methyl group]A solution of benzoic acid (1.300g, 5.172mmol) and DIPEA (1.338g, 1.803mL, 10.35mmol) in DMF (13.98mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (35mL), washed with water (2 × 50mL) and brine (1 × 50 mL). With MgSO ₄The organic layer was dried and concentrated in vacuo to give a solid. The solid was suspended in MeCN (83.89mL) at room temperature, then dibromo (triphenyl) phosphane (2.183g, 5.172mmol) and DIPEA (1.338g, 1.803mL, 10.35mmol) were added. The resulting mixture was stirred at room temperature for 2h, then concentrated in vacuo to give a solid, which was purified by silica gel column chromatography eluting with EtOAc/petroleum ether, the product fractions were combined and concentrated in vacuo to give the product as a white solid. Concentrating the mixture to obtain a solidPurification by column chromatography using ethyl acetate/petroleum ether as eluent gave the product as a white solid (924mg, 40% yield); 1H NMR (400MHz, DMSO) d 1.43(s, 9H), 4.26(m, 2H), 7.55(m, 3H), 7.80(br s, 2H), 7.97(m, 1H) and 8.45(s, 1H) ppm; MS (ES)⁺)449.08

And step 3: 3- [5- [3- (aminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine

Sodium carbonate (335.4 μ L, 2M, 0.6708mmol) was added to N- [ [3- [5- (3-amino-6-bromo-pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl)]Phenyl radical]Methyl radical]Tert-butyl carbamate (100mg, 0.2236mmol), (4-isopropylsulfonylphenyl) boronic acid (66.30mg, 0.2907mmol), palladium, triphenylphosphine (25.84mg, 0.02236mmol) in dioxane (5mL) and the mixture heated at 110 ℃ under microwave conditions for 90 min. The mixture was placed directly on a pad of silica gel, washed with diethyl ether and then with 50% EtOAc/petroleum ether. The product fractions were combined and concentrated in vacuo. The residue was dissolved in CH ₂Cl₂(10mL), TFA (764.9mg, 516.8. mu.L, 6.708mmol) was added. The reaction mixture was stirred at room temperature for 1h, then concentrated in vacuo to give an oil. It was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, 25mL/min]. Product fractions were combined and lyophilized to give the product as a yellow solid (36.05mg, 35% yield); 1H NMR (400MHz, DMSO) d1.3(d, 6H), 3.45-3.55(m, 1H), 4.24-4.3(m, 2H), 7.7-7.8(m, 2H), 7.95(d, 2H), 8.25(d, 1H), 8.3-8.4(br s, 2H), 8.4(s, 1H), 8.45(d, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)451.2

All of the following compounds were prepared using procedures analogous to those described above for compound IA-220.

The compound IA-883- [4- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxa-bisAzol-2-yl]Pyrazin-2-yl radicals]Phenyl radical]Sulfonylbutan-1-ol 1HNMR (400MHz, DMSO) d 1.21(d, 3H), 1.38-1.47(m, 1H), 1.97-2.05(m, 1H), 2.64(t, 3H), 3.38-3.46(m, 2H), 3.51-3.56(m, 1H), 4.29(t, 2H), 7.77(d, 2H), 7.97-8.01(m, 2H), 8.26(d, 2H), 8.40-8.44(m, 2H), 8.97(s, 2H) and 9.09(d, 1H) ppm; MS (ES) ⁺)495.0

Compound IA-2573- [5- [3- (aminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (2-methylsulfinylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d3.1(s, 3H), 4.3(s, 2H), 7.6-7.75(m, 4H), 8.05(d, 1H), 8.15(d, 1H), 8.35-8.5(m, 4H) and 8.9(s, 1H) ppm; MS (ES)⁺)407.1

The compound IA-3215- (3-fluoro-4-isopropylsulfonyl-phenyl) -3- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1HNMR (400MHz, DMSO) d 1.25(d, 6H), 2.7(s, 3H), 3.5-3.6(m, 1H), 4.4(s, 2H), 7.6(d, 1H), 7.7(d, 1H), 7.9(t, 1H), 8.2-8.3(m, 2H), 8.35(t, 1H), 8.9-9.0(br s, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)501.3

Compound IA-3295- (3-chloro-4-isopropylsulfonyl-phenyl) -3- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1HNMR (400MHz, DMSO) d 1.25(d, 6H), 2.7(s, 3H), 3.7-3.8(m, 1H), 4.4(s, 2H), 7.6(d, 1H), 7.7(d, 1H), 8.1(d, 1H), 8.25-8.35(m, 2H), 8.4(s, 1H), 8.9-9.0(br s, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)517.2

The compound IA-3423- [4- [ 5-amino-6- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals ]Phenyl radical]Sulfonylbutan-1-ol 1HNMR (400MHz, DMSO) d 1.25(d, 3H), 1.4-1.5(m, 1H), 1.95-2.03(m, 1H), 2.7(s, 3H), 3.4-3.5(m, 1H), 3.5-3.6(m, 1H), 4.45(s, 2H), 4.6-4.7(m, 1H), 7.6(d, 1H), 7.7(d, 1H), 8.0(d, 2H), 8.3(t, 1H), 8.4(d, 2H), 9.0(br s, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)513.2

Example 38A: 3- [5- [3- (dimethylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound IA-204)

Synthetic route

Compounds IA-204

Compounds IA-204 were prepared using method IV-AJ steps 1-3, followed by method IV-AK step 1.

Method IV-AK

Step 1: 3- [5- [3- (dimethylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine

Reacting 3- [5- [3- (aminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-Isopropylsulfonylphenyl) pyrazin-2-amine (12mg, 0.02108mmol) was added to a solution of MeI (8.976mg, 3.937. mu.L, 0.06324mmol) and potassium carbonate (8.740mg, 0.06324mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (3mL) and washed with water (1 x 5mL) and brine (1 x 5mL) in that order. With MgSO ₄The organic extracts were dried and concentrated in vacuo. The residue was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, 25mL/min]. Product fractions were combined and lyophilized to give the product as a yellow solid (3.0mg, 24% yield); 1H NMR (400MHz, MeOD) d1.35-1.4(m, 6H), 2.95(s, 6H), 4.65(s, 2H), 7.8-7.85(m, 2H), 8.05-8.1(m, 2H), 8.4-8.5(m, 4H) and 9.95(s, 1H) ppm; MS (ES)⁺)479.3

Example 39A: 5- (4-Isopropylsulfonylphenyl) -3- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine (Compound IA-276)

Synthetic route

Compound IA-276

Compound IA-276 was prepared using method IV-AJ steps 1-3 followed by method IV-AL step 1.

Method IV-AL:

step 1: 5- (4-isopropylsulfonylphenyl) -3- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine

Adding 5-bromo-3- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl to a microwave vial]Pyrazin-2-amine (75mg, 0.2218mmol), (4-isopropylsulfonylphenyl) boronic acid (50.59mg, 0.2218mmol), palladium; triphenylphosphine (12.82mg, 0.01109mmol) and aqueous sodium carbonate (332.7. mu.L, 2M, 0.6654mmol) were then added followed by DMF (1mL) and the vial was sealed. The reaction mixture was heated in a microwave at 150 ℃ for 30 min. Thereafter, water was added and the resulting precipitate was collected by filtration. The precipitate was passed through a palladium purge column eluting with MeCN and MeOH. Removal of the solvent gave the product as a yellow solid (19.2mg, 19% yield); 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 2.69(s, 3H), 3.48(t, 1H), 7.23(d, 1H), 7.92(d, 2H), 7.98(d, 2H), 8.36-8.34(m, 2H) and 9.06(s, 1H) ppm; MS (ES) ⁺)442.0

All of the following compounds were prepared using procedures analogous to those described above for compound IA-276.

Compound IA-2695- [4- (2-dimethylaminoethylsulfonyl) phenyl]-3- [5- (3-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1HNMR (400MHz, DMSO) d 2.69(s, 3H), 2.78(s, 6H), 3.36(s, 2H), 3.91-3.87: (C) ((S, C))m, 2H), 7.23(d, 1H), 7.93(d, 1H), 8.07(d, 2H), 8.39(d, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)471.0

Example 40A: [4- [5- [ 3-amino-6- [4- (dimethylaminomethyl) phenyl ] pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenyl ] methanol (compound IA-240)

Synthetic route

Compound IA-240

Compound IA-240 was prepared using method IV-C step ] -2, then using method IV-R step 1, then using method IV-AM step 1.

Method IV-AM

Step 1: [4- [5- [ 3-amino-6- [4- (dimethylaminomethyl) phenyl ] pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenyl ] methanol

4- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl ] in dry THF (1.5mL) was cooled with an ice bath]Pyrazin-2-yl radicals]-1, 3, 4-oxadiazol-2-yl]Methyl benzoate (154mg, 0.3465mmol) was then treated dropwise with DIBAL (346.5. mu.L of a 1M solution in hexane, 0.3465 mmol). The resulting mixture was stirred at 0-20 ℃ over 90min and then at room temperature overnight. DI BAL (1.732mL of 1M hexane solution, 1.732mmol) was added at room temperature. The reaction mixture was poured onto water (10mL), acidified with 2M HCl, adjusted to pH 10 with aqueous NaOH, and extracted with EtOAc (6 × 10mL) to give an orange solid. It was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH3CN) over 16 min, 25mL/min]. Combining the product fractions by carbonic acidA hydrogen salt column. The eluate was concentrated in vacuo, dissolved in acetonitrile and water, and lyophilized to give the product as a yellow powder (13.1mg, 33% yield); 1H NMR (400MHz, DMSO) d 2.18(s, 6H), 4.64(s, 2H), 5.43(br s, 1H), 4.43-4.45(m, 2H), 7.65-7.63(m, 2H), 7.69(br s, 2H), 8.05-8.30(m, 4H) and 8.92(s, 1H) ppm; MS (ES)⁺)403.18

Example 41A: 4- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-281)

Synthetic route

Compounds IA-281

Compounds IA-281 were prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AN, step 1.

Method IV-AN

Step 1: 4- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

Treatment of 4- [ 5-amino-6- [5- [4- (bromomethyl) phenyl ] with methylamine (2mL of a 33% w/w solution in ethanol)]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide (70mg, 0.1460mmol), and the resulting mixture was heated and stirred at 100 ℃ for 10 min. The reaction mixture was cooled to room temperature and filtered. The filtrate was collected, purified by preparative HPLC [ Waters Sunfire C18, 10 μ M, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were passed through a bicarbonate column with MeOH/CH₂Cl₂And (4) eluting. The eluent was concentrated in vacuo and the solid triturated with acetonitrile to give the product as a yellow solid (11.4mg, 19% yield); 1HNMR (400MHz, DMSO) d 2.30(s, 3H), 2.98-3.02(m, 6H), 3.77(s, 2H), 7.55(d, 2H), 7.61(d, 2H), 7.78(br s, 2H), 8.11(d, 2H), 8.17(d, 2H) and 8.98(s, 1H) ppm; MS (ES)⁺)430.31

Example 42A: acetic acid [4- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl ] pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenyl ] methyl ester (compound IA-131)

Synthetic route

Compound IA-131

Compounds IA-131 were prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AO, step 1.

Process IV-AO

Step 1: acetic acid [4- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl ] pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenyl ] methyl ester

4- [ 5-amino-6- [5- [4- (bromomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide (200mg, 0.4172mmol) and potassium acetate (102.4mg, 1.043 mmo) ]-l) mixture in DMF (5.714mL) was heated at 100 ℃ for 4h in a sealed microwave tube. The reaction mixture was cooled to room temperature, poured onto ice/water and acidified with HCl (1.043mL, 1M, 1.043 mmol). The mixture was extracted with ethyl acetate (3 × 10mL) and the combined organic extracts were washed with brine (3 × 10 mL). With MgSO₄The extract was dried and concentrated under reduced pressure to give a yellow solid (150mg, 74% yield); 1H NMR (400MHz in DMSO) d 2.13(s, 3H), 2.98-3.02(m, 6H), 5.22(s, 2H), 7.55(d, 2H), 7.66 (m), (md, 2H), 7.78(br s, 2H), 8.16-8.19(m, 4H) and 8.99(s, 1H) ppm; MS (ES)⁺)459.18

Example 43A: 4- [ 5-amino-6- [5- [4- (hydroxymethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-76)

Synthetic route

Compound IA-76

Compound IA-76 was prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AO, step 1, then using method IV-AP, step 1.

Method IV-AP

Step 1: 4- [ 5-amino-6- [5- [4- (hydroxymethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

Reacting acetic acid [4- [5- [ 3-amino-6- [4- (dimethylcarbamoyl) phenyl group ]Pyrazin-2-yl radicals]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methyl ester (118mg, 0.2445mmol) was suspended in methanol (2mL) and treated with NaOH (489.0 μ L, 1M, 0.4890 mmol). The resulting mixture was stirred at 55 ℃ for 1 h. The reaction mixture was cooled to room temperature and then neutralized with HCl (978.0 μ L, 1M, 0.9780mmol), filtered and washed with acetonitrile. The resulting yellow powder was heated in acetonitrile (5mL), cooled, and filtered to give a pale yellow powder. It was purified by silica gel column chromatography with 5% MeOH/CH₂Cl₂Elution afforded the product as a pale yellow powder (73mg, 70%); 1H NMR (400MHz, DMSO) d 2.98-3.02(m, 6H), 4.64(d, 2H), 5.44(t, 1H), 7.54-7.62(dd, 4H), 7.78(br s, 2H), 8.12-8.18(dd, 4H) and 8.98(s, 1H) ppm; MS (ES)⁺)417.23

Example 44A: 4- [ 5-amino-6- [5- [4- (1, 2-dihydroxyethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IA-106)

Synthetic route

Compounds IA-106

Compounds IA-106 were prepared using method IV-C, steps 1-2, then using method IV-R, step 1, then using method IV-AQ, step 1.

Process IV-AQ

Step 1: 4- [ 5-amino-6- [5- [4- (1, 2-dihydroxyethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide

AD-mixture-alpha (450mg, ca.) and methanesulfonamide (20.53mg, 0.2158mmol) in a mixture of tert-butanol (2 mL)/water (2mL) were stirred at room temperature to dissolve, then cooled to 0 ℃ with 4- [ 5-amino-6- [5- (4-vinylphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzamide (89mg, 0.2158 mmol). The reaction mixture was stirred vigorously and allowed to warm to room temperature overnight. A further portion of the AD-mixture (300g) was added and the reaction mixture was stirred at room temperature overnight to complete the conversion. With Na₂S₂O₃The reaction mixture was treated with NaCl solution, extracted into ethyl acetate (10mL), and MgSO₄Dried and concentrated under reduced pressure to give a yellow solid. It was purified by reverse phase preparative HPLC [ waters sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were combined and lyophilized to give the product as a pale yellow powder (28.4mg, 36% yield); 1H NMR (400MHz, DMSO) d 2.9-3.02(m, 6H), 3.51(m, 2H), 4.67(m, 1H), 4.83(m, 1H), 5.49(m, 1H), 7.55(d, 2H), 7.64(d, 2H), 7.78(br s, 2H), 8.11(d, 2H), 8.18(d, 2H) and 8.98(s, 1H) ppm; MS (ES) ⁺)447.25

Example 45A: 3- [5- [4- (aminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound IA-222)

Synthetic route

Compounds IA-222

Compound IA-222 was prepared using method IV-C, steps 1-2, followed by method IV-AR, steps 1-3.

Method IV-AR

Step 1: 4- (2- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carbonyl) hydrazinecarbonyl) benzyl carbamic acid tert-butyl ester

3-amino-6- (4-isopropylsulfonylphenyl) pyrazine-2-carboxylic acid hydrazide (100mg, 0.2833mmol) and 4- [ (tert-butoxycarbonylamino) methyl ] benzoic acid (71.19mg, 0.2833mmol) in dmf (1.000mL) was treated with triethylamine (28.67mg, 39.49. mu.L, 0.2833mmol) followed by TBTU (109.2mg, 0.3400mmol) and the resulting solution was stirred at room temperature overnight. The solution was poured dropwise onto rapidly stirred water (15ml), stirred at room temperature for 1h, then filtered to give the product as a pale yellow solid, dried under high vacuum at 83 ℃ and used in the next step without further purification (136mg, 84%)

Step 2: 4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) benzylcarbamic acid tert-butyl ester

Using dibromo (triphenyl) phosphane (b) at 0 ℃143.5mg, 0.3400mmol) tert-butyl 4- (2- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carbonyl) hydrazinecarbonyl) benzylcarbamate (136mg, 0.24mmol) and a mixture of DIPEA (109.8mg, 148.0 μ L, 0.8499mmol) in acetonitrile (3.000mL) was worked up stepwise and the resulting mixture was stirred at room temperature for 48 h. The mixture was concentrated in vacuo to pre-adsorb onto silica gel and purified by silica gel column chromatography using 50% EtOAc/CH₂Cl₂Elution gave the product (46.8mg, 30% yield); MS (ES)⁺)551.31

And step 3: 3- [5- [4- (aminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine

Treatment of N- [ [4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] with TFA (1mL, 12.98mmol)]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methyl radical]Tert-butyl carbamate (45mg, 0.08172mmol) in CH₂Cl₂(1mL) was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure and then reacted with methanol/CH₂Cl₂(x 2) co-boiling together, dissolving in CH₂Cl₂MeOH, passed through a carbonate column. The eluate was concentrated and then crystallized from hot acetonitrile to give a yellow crystalline solid (18mg, 41% yield); 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 1.97(br s, 2H), 3.47(m, 1H), 3.85(s, 2H), 7.63(d, 2H), 7.89(br s, 2H), 7.98(d, 2H), 8.11(d, 2H), 8.40(d, 2H) and 9.06(s, 1H) ppm; MS (ES) ⁺)451.41

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-222.

Compound I A-803- [5- [3- [ (1R) -1-aminoethyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.19(m, 6H), 1.32(m, 3H), 3.48(m, 1H), 4.17(m, 1H), 7.61(m, 1H), 7.69(m, 1H), 7.99(m, 5H), 8.19(m, 1H), 8.39(m, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)465.32

Compound IA-845- (4-isopropylsulfonylphenyl) -3- [5- (3-pyrrolidin-2-ylphenyl) -1,3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.19(m, 6H), 1.57(m, 1H), 1.80(m, 2H), 2.20(m, 1H), 2.97(m, 1H), 3.01(m, 1H), 3.45(m, 1H), 4.24(m, 1H), 7.59(m, 1H), 7.67(m, 1H), 7.97-8.03(m, 4H), 8.19(s, 1H), 8.39(m, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)491.33

The compound IA-913- [5- (3-aminopropyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.18-1.20(m, 7H), 1.23(s, 1H), 1.99(t, 2H), 3.46(t, 1H), 7.16(s, 1H), 7.87(d, 2H), 8.46(d, 2H), 8.93(s, 1H) and 10.20(s, 1H) ppm; MS (ES) ⁺)403.23

Compound IA-923- [5- (4-aminobutyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.18-1.20(m, 7H), 1.50(t, 2H), 1.84(t, 2H), 2.62(t, 2H), 3.03(t, 3H), 3.46(t, 1H), 7.85(br s, 1H), 7.96(d, 2H), 8.31(d, 2H) and 9.02(s, 1H) ppm; MS (ES)⁺)417.23

The compound IA-1025- (4-isopropylsulfonylphenyl) -3- [5- (4-pyrrolidin-2-ylphenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.20(d, 6H), 1.45-1.58(m, 1H), 1.71-1.86(m, 2H), 2.15-2.26(m, 1H), 2.90-3.08(m, 2H), 3.48(m, 1H), 4.18(t, 1H), 7.65(d, 2H), 7.97(br s, 2H), 7.98(d, 2H), 8.09(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)491.34

Compound IA-1073- [5- [4- (2-aminoethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.20(d, 6H), 2.79(m, 2H), 2.85(m, 2H), 3.47(m, 1H), 7.51(d, 2H), 7.92(br s, 2H), 7.98(d, 2H), 8.09(d, 2H), 8.39(d, 2H) and 9.06(s, 1H) ppm; MS (ES)⁺)465.34

The compound IA-1233- [5- [3- [ (1S) -1-aminoethyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl ]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.19(m, 6H),1.32(m, 3H), 3.49(m, 1H), 4.18(m, 1H), 7.61(m, 1H), 7.69(m, 1H), 7.99(m, 4H), 8.19(m, 1H), 8.39(m, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)465.32

Compound IA-1243- [5- [4- [ (1R) -1-aminoethyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 1.30(d, 3H), 3.48(m, 1H), 4.11(q, 1H), 7.67(d, 2H), 7.96(v br s, 2H), 7.98(d, 2H), 8.10(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)465.37

Compound IA-1303- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.3(d, 6H), 2.7(s, 3H), 3.4-3.6(m, 1H), 4.35(s, 2H), 7.6(d, 1H), 7.7(d, 1H), 8.0(d, 2H), 8.3(t, 1H), 8.38(d, 2H), 8.92(br s, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)483.4

The compound IA-1455- (4-isopropylsulfonylphenyl) -3- [5- (1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.19(m, 6H), 2.89(m, 2H), 3.08(m, 2H), 3.47(m, 1H), 4.03(s, 1H), 7.34(m, 1H), 7.90-7.99(m, 5H), 8.26(s, 1H), 8.38(m, 2H) and 9.03(s, 1H) ppm; MS (ES) ⁺)477.41

The compound IA-1475- (4-isopropylsulfonylphenyl) -3- [5- (5-pyrrolidin-2-yl-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.25(d, 6H), 2.0-2.2(m, 3H), 3.3-3.6(m, 4H), 5.0-5.1(m, 1H), 7.9-8.0(m, 4H), 8.4(d, 2H), 9.05-9.1(m, 2H) and 9.6(br s, 1H) ppm; MS (ES)⁺)497.4

Compound I A-1683- [5- (aminomethyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.16-1.19(m, 6H), 1.23(s, 3H), 3.46(t, 1H), 4.06(s, 2H), 7.96(d, 2H), 8.31(d, 2H) and 9.02(s, 1H) ppm; MS (ES)⁺)375.17

Compound I A-1733- [5- [5- (aminomethyl) -2-thienyl ]]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 3.46-3.51(m, 1H), 4.41(s, 2H), 7.45(d, 1H), 7.96(d, 1H), 7.98(d, 2H), 8.30(br s, 2H), 8.37(d, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)457.3

Compounds IA-1853- [5- [3- (azetidin-3-yl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 3, 48(m, 1H), 4.19(m, 2H), 4.34(m, 3H), 7.71-7.79(m, 2H), 7.97(m, 2H), 8.12(m, 1H), 8.20(m, 1H), 8.41(m, 2H), 8.69(br s, 1H) and 9.09(s, 1H) ppm; MS (ES) ⁺)477.29

Compound IA-2013- [5- (4-aminophenyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.21(d, 6H), 3.47(m, 1H), 6.10(s, 2H), 6.75(d, 2H), 7.83(d, 2H), 7.89(br s, 2H), 7.97(d, 2H), 8.39(d, 2H) and 9.02(s, 1H) ppm; MS (ES)⁺)437.22

The compound IA-2143- [5- (2-aminoethyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.19(d, 6H), 3.05(m, 4H), 3.33(d, 1H), 3.46(s, 1H), 7.96(d, 2H), 8.31(d, 2H) and 9.02(s, 1H) ppm; MS (ES)⁺)389.24

The compound IA-2283- [5- [4- [ (1S) -1-aminoethyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 1.30(d, 3H), 3.48(m, 1H), 4.11(q, 1H), 7.67(d, 2H), 7.96(v br s, 2H), 7.98(d, 2H), 8.10(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)465.42

The compound IA-2325- (4-isopropylsulfonylphenyl) -3- [5- (1, 2, 3, 6-tetrahydropyridin-4-yl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.19(d, 6H), 2.50(s, 2H), 2.98(br t, 2H), 3.46(m, 1H), 3.55(drd, 2H), 7.03(s, 1H), 7.90(br s, 2H), 7.95(d, 2H), 8.35(d, 2H) and 9.04(s, 1H) ppm; MS (ES) ⁺)427.4

The compound IA-2823- [5- [3- (1-aminoethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.20(m, 6H), 1.33(m, 3H), 3.48(m, 1H), 4.18(m, 1H), 7.61(m, 1H), 7.70(m, 1H), 7.98-8.03(m, 4H), 8.20(m, 1H), 8.39(m, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)465.3

The compound IA-2853- [5- [4- (azetidin-3-yl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.20 (d, 6H), 3.48(m, 1H), 3.65(m, 2H), 3.87(m, 2H), 3.99(m, 1H), 7.65(d, 2H), 7.91(br s, 2H), 7.98(d, 2H), 8.14(d, 2H), 8.39(d, 2H) and 9.06(s, 1H) ppm; MS (ES)⁺)477.44

Compound IA-3063- [5- [ 2-chloro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine MS (ES)⁺)499.2

Compound IA-3093- [5- [ 3-chloro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.25(d, 6H), 2.7(s, 3H), 3.4-3.5(m, 1H), 4.45(s, 2H), 7.7(d, 1H), 8.0(d, 2H), 8.3(d, 1H), 8.4(d, 2H), 9.0(br s, 2H) and 9.1(s, 1H) ppm; MS (ES) ⁺)499.2

Compound IA-3113- [5- [4- (1-amino-1-methyl-ethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.19(m, 6H), 1.43(s, 6H), 3.51(m, 1H), 7.83(m, 2H), 7.97(m, 2H), 8.09(m, 2H), 8.39(m, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)479.27

Example 46A: 2- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenol (compound IA-235)

Synthetic route

Compound IA-235

Compound IA-235 was prepared using method IV-C, step 1-2, then using method IV-X, step 1-2, then using method IV-AS, step 1.

Method IV-AS

Step 1: 2- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenol

Li OH (292.0. mu.L, 1M, 0.2920mmol) was added to a mixture of 2- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) phenyl acetate (14mg, 0.02920mmol) in THF (5mL) at ambient temperature. After 3h, an additional portion of LiOH (292.0. mu.L, 1M, 0.2920mmol) was added and the reaction was stirred for 1h at room temperature. 1M HCl was added dropwise to acidity and the resulting precipitate was isolated by filtration. The solid residue was dissolved in a mixture of MeCN and water and lyophilized to give the product as a green solid (5.1mg, 38% yield); 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 3.46(m, 1H), 6.98-7.22(m, 2H), 7.36-7.59(m, 1H), 7.75-8.16(m, 5H), 8.37(d, 2H), 9.06(s, 1H) and 10.43(s, 1H) ppm; MS (ES) ⁺)438.2

All of the following compounds were prepared using procedures analogous to those described above for compound IA-235.

Compound IA-1934- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenol 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 3.47(m, 1H), 7.03(dd, 2H), 7.89(br s, 2H), 7.97(dd, 2H), 8.02(dd, 2H), 8.39(dd, 2H), 9.04(s, 1H) and 10.44(s, 1H) ppm; MS (ES)⁺)438.2

Example 47A: 5- (4-Isopropylsulfonylphenyl) -3- [5- [4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine (compound IA-159)

Synthetic route

Compounds IA-159

Compound IA-159 was prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AT, step 1.

Method IV-AT

Step 1: 5- (4-Isopropylsulfonylphenyl) -3- [5- [4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine

Reacting MeNH₂Was added to 3- [5- [4- (bromomethyl) phenyl ] ethyl ester (184.9g, 243.6mL, 33% w/w, 1.965mol) in one portion]-1, 3, 4-oxadiazol-2-yl]-5- (4-Isopropylsulfonylphenyl) pyrazin-2-amine (10.11g, 19.65mmol) in CH₂Cl₂(1.01L) and methanol (1.01L), and the resulting mixture was stirred at room temperature overnight. Nitrogen was bubbled through the reaction for 2h, then the reaction mixture was concentrated in vacuo. Placing the crude material in K ₂CO₃(393.0mL, 0.25M, 98.25mmol) for 2h, then isolated by filtration and washed with water. Trituration with warm acetonitrile afforded the product as a yellow solid (7.19g, 75% yield); 1H NMR (400MHz, DMSO) d 1.19-1.21(d, 6H), 2.30(m, 3H), 3.35-3.49(m, 1H), 3.77(m, 2H), 7.61-7.63(d, 2H), 7.97-7.99(d, 2H), 8.11-8.13(d, 2H), 8.39-8.41(d, 2H) and 9.06(s, 1H) ppm; MS (ES)⁺)465.4

All of the following compounds were prepared using procedures analogous to those described above for compounds IA-159.

The compound IA-1195- (4-isopropylsulfonylphenyl) -3- [5- [4- [ (2-methoxyethylamino) methyl ] amide]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 2.67(t, 2H), 3.25(s, 3H), 3.43(t, 2H), 3.48(m, 1H), 3.84(s, 2H), 7.62(d, 2H), 7.97(d, 2H), 7.98(v brs, 2H), 8.12(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)509.37

Compound IA-1223- [5- [4- (ethylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.17-1.22(m, 9H), 2.89(q, 2H), 3.48(m, 1H), 4.15(s, 2H), 7.77(d, 2H), 7.98(d, 2H), 7.99(br s, 2H), 8.21(d, 2H), 8.41(d, 2H) and 9.08(s, 1H) ppm; MS (ES) ⁺)479.41

Compounds IA-1392- [ [4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methylamino radical]-2- (hydroxymethyl) propane-1, 3-diol 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 3.44(s, 6H), 3.45(m, 1H), 3.90(s, 2H), 4.37(br s, 3H), 7.66(d, 2H), 7.95(br s, 2H), 7.98(d, 2H), 8.11(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)555.32

The compound IA-1465- (4-isopropylsulfonylphenyl) -3- [5- [3- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.19(d, 6H), 2.33(s, 3H), 3.48(m, 1H), 3.83(s, 2H), 7.61-7.67(m, 2H), 7.97(m, 3H), 8.05(m, 1H), 8.15(m, 1H), 8.39(m, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)465.29

Compound IA-1583- [5- [4- [ (cyclopropylamino) methyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 0.28(m, 2H), 0.36(m, 2H), 1.20(d, 6H), 2.07(m, 1H), 3.48(m, 1H), 3.85(s, 2H), 7.61(d, 2H), 7.96(br s, 2H), 7.98(d, 2H), 8.11(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)491.42

Compounds IA-1782- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) benzylamino) ethanol 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 2.61(t, 2H), 3.42-3.51(m, 3H), 3.86(s, 2H), 4.54(br s, 1H), 7.63(d, 2H), 7.80(br s, 2H), 7.98(d, 2H), 8.12(d, 2H), 8.39(d, 2H) and 9.06(s, 1H) ppm; MS (ES) ⁺)495.31

Compounds IA-225N- [ [4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methyl radical]-N ', N' -dimethyl-ethane-1, 2-diamine 1H NMR (400MHz, DMSO) d1.20(d, 6H), 3.07(s, 3H), 3.29-3.49(m, 5H), 4.74(s, 2H), 7.91(d, 2H), 7.97(d, 2H), 7.98(vbr s, 2H), 8.27(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)522.23

Compound IA-238[4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methanol 1H NMR (400MHz, DMSO) d1.20(d, 6H), 3.48(m, 1H), 6.64(d, 2H), 5.46(t, 1H), 7.61(d, 2H), 7.98(d, 2H), 7.99(br s, 2H), 8.15(d, 2H), 8.40(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)452.26

Compound IA-2433- [5- [4- (dimethylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.20 (m, 6H), 2.21(s, 6H), 3.47(m, 1H), 3.54(s, 2H), 7.59(d, 2H), 7.90(br s, 2H), 7.97(d, 2H), 8.13(d, 2H), 8.39(d, 2H) and 9.06(s, 1H) ppm; MS (ES)⁺)479.37

Compounds IA-333(R) -2- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) -3-fluorobenzylamino) propan-1-ol 1HNMR (400MHz, DMSO) d 1.06(3H, d), 1.20(d, 6H), 2.44(m, 1H), 3.35 (masked, 2H), 3.48(m, 1H), 3.85(m, 2H), 4.53(m, 1H), 7.47(d, 1H), 7.52(d, 1H), 7.97(br s, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.08(s, 1H) ppm; MS (ES) ⁺)527.2

Compounds IA-334(S) -1- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) -3-fluorobenzylamino) propan-2-ol 1HNMR (400MHz, DMSO) d 1.06(d, 3H), 1.20(d, 6H), 3.45(m, 1H), 3.71(m, 1H), 4.53(d, 1H), 7.46(d, 1H), 7.52(d, 1H), 7.97(br S, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.07(S, 1H) ppm; MS (ES)⁺)527.2

Compounds IA-335(S) -2- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) -3-fluorobenzylamino) propan-1-ol 1HNMR (400MHz, DMSO) d 0.97(d, 3H), 1.20(d, 6H), 2.62(m, 1H), 3.30(m, 2H), 3.48(m, 1H), 3.88(m, 2H), 4.58(m, 1H), 7.47(d, 1H), 7.53(d, 1H), 7.97(br S, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.07(S, 1H) ppm; MS (ES)⁺)527.2

Compound IA-3363- [5- [ 3-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.20(m, 6H), 2.68(m, 3H), 3.48(m, 1H), 4.34(m, 2H), 7.86(t, 1H), 7.99(m, 2H), 8.09(m, 1H), 8.14(dd, 1H), 8.42(m, 2H), 8.96(br s, 2H) and 9.11(s, 1H) ppm; MS (ES) ⁺)483.1

Compound IA-3403- [5- [ 2-fluoro-4- [ (2-fluoroethylamino) methyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1HNMR (400MHz, DMSO) d 1.20(d, 6H), 2.81(m, 2H), 3.48(m, 1H), 3.88(s, 2H), 4.51(m, 2H), 7.47(d, 1H), 7.52(d, 1H), 7.97(br s, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)515.2

Compounds IA-341(R) -1- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) -3-fluorobenzylamino) propan-2-ol 1HNMR (400MHz, DMSO) d 1.06(dd, 3H), 1.20(dd, 6H), 3.45(m, 1H), 3.71(m, 1H), 4.53(m, 1H), 7.46(d, 1H), 7.52(d, 1H), 7.97(br s, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.07(s, 1H))ppm；MS(ES⁺)527.2

The compound IA-3453- [5- [ 2-fluoro-4- [ (tetrahydrofuran-3-ylamino) methyl ] -methyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1HNMR (400MHz, DMSO) d 1.20(d, 6H), 1.70-1.74(m, 1H), 1.90-1.98(m, 1H), 3.25-3.32(m, 1H), 3.41-3.50(m, 2H), 3.60-3.85(m, 5H), 7.47(d, 1H), 7.53(d, 1H), 7.97(br s, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.08(s, 1H) ppm; MS (ES) ⁺)539.3

The compound IA-3463- [5- [4- [ (2-fluoroethylamino) methyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 2.82(m, 2H), 3.48(m, 1H), 3.87(s, 2H), 4.50(m, 2H), 7.64(d, 2H), 7.97(br s, 2H), 7.98(d, 2H), 8.13(d, 2H), 8.40(d, 2H) and 9.06(s, 1H) ppm; MS (ES)⁺)497.2

Compounds IA-3481- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) -3-fluorobenzylamino) -2-methylpropan-2-ol 1H NMR (400MHz, DMSO) d 1.13(s, 6H), 1.20(d, 6H), 2.39(s, 2H), 3.48(m, 1H), 3.88(s, 2H), 4.27(s, 1H), 7.45(d, 1H), 7.51(d, 1H), 7.97(br s, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)541.2

Compound IA-3193- [5- [ 2-fluoro-4- [ (oxetan-3-ylamino) methyl]Phenyl radical]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1HNMR (400MHz, DMSO) d 1.20(d, 6H), 4.48(m, 1H), 3.77(s, 2H), 3.80(m, 1H), 4.34(t, 2H), 4.59(t, 2H), 7.45(d, 1H), 7.51(d, 1H), 7.97(brs, 2H), 7.98(d, 2H), 8.12(t, 1H), 8.37(d, 2H) and 9.07(s, 1H) ppm; MS (ES) ⁺)525.2

Example 48A: 4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] benzamidine (Compound IA-70)

Synthetic route

Compound IA-70

Preparation of Compounds IA-70 Using methods IV-C, Steps 1-2, followed by methods IV-R, step 1, followed by methods IV-AU, step 1

Method IV-AU

Step 1: 4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] benzamidine

4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Benzonitrile (58mg, 0.1299mmo l) was suspended in CH₂Cl₂(3 mL)/ethanol (4mL, 68.51mmol) and then sonicated to saturation during the addition of HCl gas at 0 ℃. The resulting suspension was stirred at room temperature for 4h, then warmed to 40 ℃ and stirred overnight. The mixture was concentrated to dryness, dried under reduced pressure, then suspended in absolute ethanol (60ml), cooled with an ice bath and ammonia gas was bubbled for 5 min. The reaction vessel was sealed and then stirred at room temperature for 3h, then heated at 50 ℃ overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH) ₃CN) within 16 minutes, 25mL/min]. The product fractions were combined and lyophilized to give the product as a pale yellow powder (16.7mg, 32% yield); 1HNMR (400MHz, DMSO) d 1.21(d, 6H), 3.48(m, 1H), 6.80(br s, 2H), 7.98(d, 2H), 8.05(d, 2H), 8.21(d, 2H), 8.41(d, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)464.24

All of the following compounds were prepared using procedures analogous to those described above for compound IA-70.

Compound IA-2084- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]-N-methyl-benzamidine 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 2.88(s, 3H), 3.48(m, 1H), 6.83(br s, 1H), 7.98(br s, 2H), 7.99(d, 2H), 8.03(d, 2H)8.19(d, 2H), 8.41(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)478.24

Example 49A: 4- [5- [ 3-amino-6- [4- (2-dimethylaminoethylsulfonyl) phenyl ] pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenol (compound IA-191)

Synthetic route

Compound IA-191

Compound IA-191 was prepared using method IV-AJ step 1-2 followed by method IV-AV step 1.

Method IV-AV

Step 1: 4- [5- [ 3-amino-6- [4- (2-dimethylaminoethylsulfonyl) phenyl ] pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenol

2- (4-bromophenyl) sulfonyl-N, N-dimethyl-ethylamine (181.8mg, 0.6221mmol) was dissolved in dioxane (2mL) and pinacol ester diboron (237.0mg, 0.9332mmol) and potassium acetate (183.1mg, 1.866mmol) were added. The reaction mixture was degassed, purged with nitrogen (5X), and then Pd (dppf) Cl was added₂.CH₂Cl₂(50.80mg, 0.06221mmol) and the reaction was heated to 90 ℃ for 2 h. The reaction mixture was cooled to ambient temperature and diluted with DMF (2 mL). Adding acetic acid [4- [5- (3-amino-6-bromo-pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl]Phenyl radical]Ester (234mg, 0.6221mmol), Na₂CO₃(933.0 μ L of a 2M aqueous solution, 1.866)mmol) and Pd (PPh)₃)₂Cl₂(43.67mg, 0.06221mmol), the reaction was heated at 150 ℃ for 30 minutes under microwave conditions. The reaction mixture was partitioned between EtOAc (5mL) and water (5mL), and any precipitate was removed by filtration. Separate the layers, extract the aqueous layer with EtOAc (3X 5mL), MgSO₄The combined organic extracts were dried, filtered, and concentrated in vacuo. The residue was triturated from EtOAc/MeOH to give the title compound as a brown solid (44.3mg, 15%); 1HNMR (400MHz, DMSO) d 2.07(s, 6H), 2.56(t, 2H), 3.52(t, 2H), 7.03(d, 2H), 7.87(br s, 2H), 8.02(dd, 4H), 8.38(d, 2H), 9.05(s, 1H) and 10.44(s, 1H) ppm; MS (ES) ⁺)467.2

Example 50A: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-amine (compound IA-270)

Synthetic route

Compound IA-270

Compound IA-270 was prepared using method IV-B, step 1-2, followed by method IV-AW step 1-2.

Method IV-AW

Step 1: 2- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carbonyl) hydrazine thiocarboxamide

TBTU (749.4mg, 2.334mmol) and Et₃N (157.5mg, 216.9 μ L, 1.556mmol) was added to a suspension of 3-amino-6- (4-isopropylsulfonylphenyl) pyrazine-2-carboxylic acid (500mg, 1.556mmol) and thiosemicarbazide (141.8mg, 1.556mmol) in DMF (10 mL). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was added to rapidly stirred water and the resulting precipitate isolated by filtration to give the product as a tan solid (587mg, 96%) 1H NMR (400M)Hz, DMSO) d 1.18(d, 6H), 3.40-3.56(m, 1H), 7.64(s, 2H), 7.79(s, 2H), 7.88(d, 2H), 8.56(d, 1H), 9.03(s, 1H), 9.41(s, 1H) and 10.75(s, 1H) ppm; MS (ES)⁺)395.2

Step 2: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-amine

EDC (109.3mg, 0.5704mmol) was added to [ [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazine-2-carbonyl ]Amino group]Thiourea (150mg, 0.3803mmol) in DCE (3.000mL) was added to a stirred suspension and the reaction mixture was heated at reflux for 22 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3X 10mL) over MgSO₄The combined organic extracts were dried, filtered, and concentrated in vacuo to give the sub-title compound as a yellow solid (118mg, 86%) 1H NMR (400MHz, DMSO) d1.19(d, 6H), 3.45(dt, 1H), 7.65-7.80(m, 4H), 7.95(d, 2H), 8.26(d, 2H), and 8.89(s, 1H) ppm; MS (ES)⁺)361.0

Example 51: 3- [5- [5- (ethylaminomethyl) -2-thienyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound IA-83)

Synthetic route

Compound IA-83

Compound IA-83 was prepared using method IV-C, step 1-2, then using method IV-X, step 1-2, then using method IV-AX, step 1-3.

Process IV-AX

Step 1: di-tert-butyl N- [5- (4-isopropylsulfonylphenyl) -3- [5- (5-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-yl ] iminodicarbonate

Reacting 5- (4-isopropylsulfonylphenyl) -3- [5- (5-methyl-2-thienyl) -1, 3, 4-oxadiazole-2-yl]Pyrazin-2-amine (600mg, 1.359mmol) was added to MeCN (50mL) followed by BOC ₂O (889.8mg, 936.6. mu.L, 4.077mmol) and DMAP (8.301mg, 0.06795 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a solid which was purified by silica gel column chromatography eluting with 50% EtOAc/petroleum ether (544.6mg, 74%) 1H NMR (400MHz, CDCl)₃) d 1.29(d, 6H), 1.36(s, 9H), 2.54(s, 3H, 3.20(m, 1H), 6.83(m, 1H), 7.71(m, 1H), 8.03(m, 2H), 8.31(m, 2H) and 9.06(s, 1H) ppm

Step 2: 3- (5- (5- (bromomethyl) thiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) -5- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yliminodicarbonate di-tert-butyl ester

To N- [5- (4-isopropylsulfonylphenyl) -3- [5- (5-methyl-2-thienyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]To a solution of di-tert-butyl iminodicarbonate (700mg, 1.292 mmol) in ethyl acetate (50mL) was added NBS (299.0mg, 1.680mmol) and AIBN (42.43mg, 0.2584 mmol). The resulting mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, filtered, washed with water, and MgSO₄The organic layer was dried and concentrated in vacuo to give a yellow solid which was used in the next step without further purification.

And step 3: 3- [5- [5- (ethylaminomethyl) -2-thienyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine

To a solution of di-tert-butyl 3- (5- (5- (bromomethyl) thiophen-2-yl) -1, 3, 4-oxadiazol-2-yl) -5- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yliminodicarbonate (90mg, 0.1450mmol) in ethanol (2mL) was added ethylamine (7.250mL of a 2M ethanol solution, 14.50mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give a solid. Redissolving the solid in CH₂Cl₂And concentrated to a solid to remove any remaining methanol. Dissolving the solid in CH₂Cl₂(3mL), TFA (165.3mg, 111.7. mu.L, 1.450mmol) was added. The mixture was stirred at room temperature for 2h, then concentrated in vacuo, and the residue was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were combined and lyophilized to give the product as a pale yellow powder (63mg, 73.5%); 1H NMR (400MHz, DMSO) d 1.20-1.25(m, 9H), 3.0-3.1(m, 2H), 3.42-3.46(m, 1H), 4.5(s, 2H), 7.5(d, 1H), 7.95(d, 1H), 8.01(d, 1H), 8.38(d, 1H), 9.0(br s, 2H) and 9.18(s, 1H) ppm; MS (ES)⁺)485.4

All of the following compounds were prepared using a procedure analogous to that described above for compounds I A-83.

The compound IA-1405- (4-isopropylsulfonylphenyl) -3- [5- [5- (methylaminomethyl) -2-thienyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.22(d, 6H), 2.65(s, 3H), 3.42-3.46(m, 1H), 4.5(s, 2H), 7.5(d, 1H), 8.0(d, 1H), 8.05(d, 1H), 8.4(d, 1H), 9.05(br s, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)471.3

The compound IA-2265- (4-isopropylsulfonylphenyl) -3- [5- [4- (methylaminomethyl) -2-thienyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400MHz, MeOD) d 1.4(d, 6H), 2.8(s, 3H), 4.4(s, 2H), 3.3-3.4(m, 1H), 8.0-8.1(m, 3H), 8.12(s, 1H), 8.35(d, 2H) and 9.0(s, 1H) ppm; MS (ES)⁺)471.3

The compound IA-2363- [5- [5- [ (2, 2-difluoroethylamino) methyl]-2-thienyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1HNMR (400MHz, DMSO) d 1.25(d, 6H), 3.4-3.6(m, 3H), 4.55(s, 2H), 6.2-6.5(m, 1H), 7.5(d, 1H), 7.8-8.1(m, 4H), 8.45(d, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)521.3

Compound IA-2483- [5- [5- [ (isopropylamino) methyl ] methyl]-2-thienyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1HNMR (400MHz, DMSO) d 1.25(m, 6H), 1.35(d, 6H), 3.4-3.6(m, 2H), 4.6(s, 2H), 7.5(d, 1H), 7.95-8.1(m, 4H), 8.45(d, 2H), 8.9-9.0(br s, 2H) and 9.1(s, 1H) ppm; MS (ES) ⁺)499.4

Example 52A: n- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] acetamide (Compound IA-177)

Synthetic route

Compound IA-177

Compound IA-177 was prepared using method I V-C, step 1-2, followed by method IV-AY, step 1-2.

Process IV-AY

Step 1: n- (2- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carbonyl) hydrazine thiocarbonyl) acetamide

A mixture of 3-amino-6- (4-isopropylsulfonylphenyl) pyrazine-2-carboxylic acid hydrazide (100mg, 0.2982mmol), acetyl isothiocyanate (30.16mg, 26.20. mu.L, 0.2982mmol) and dry DCE (2.000mL) was stirred at ambient temperature for 2h and then concentrated in vacuo. It was used in the next step without further purification; MS (ES)⁺)437.20

Step 2: n- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] acetamide

N- (2- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carbonyl) hydrazinecarbonothioyl) acetamide (47mg, 0.1077mmol) was dissolved in DMF (2mL) and EDC (30.98mg, 0.1616mmol) was added. The reaction system is stirred at ambient temperature45 minutes and then warmed to 100 ℃ for 1 hour. The reaction mixture was cooled to ambient temperature and then slowly added to stirred water. The resulting precipitate was isolated by filtration to give the sub-title product as a yellow solid (31mg, 68%); 1HNMR (400MHz, DMSO) d 1.18(d, 6H), 2.20(s, 3H), 3.41-3.49(m, 1H), 7.81(br s, 2H), 8.14(d, 2H), 8.27(d, 2H), 8.99(s, 1H) and 11.98(s, 1H) ppm; MS (ES) ⁺)403.2

Example 53A: 2-amino-N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] acetamide (Compound IA-82)

Synthetic route

Compound IA-82

Compound IA-82 was prepared using method IV-C, step 1-2, then using method IV-AY, step 1-2, then using method IV-AZ, step 1.

Process IV-AZ

Step 1: 2-amino-N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] acetamide

Hydrazine hydrate (8.065mg, 7.838. mu.L, 0.1611mmol) was added to N- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) -2- (1, 3-dioxoisoindolin-2-yl) acetamide (147mg, 0.1611mmol) in MeOH (5mL)/CH₂Cl₂(5mL) and the reaction mixture was stirred at ambient temperature for 2 hours. A further portion of hydrazine hydrate (16.13mg, 15.68. mu.L, 0.3222mmol) was added and the reaction stirred for a further 16 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected and lyophilized to give the title compound as a yellow solid (10mg, 11%); 1H NMR (400.0MHz, DMSO) d1.18(d, 6H), 3.50-3.53(m, 1H), 4.11(s, 1.4H), 4.33(s, 0.6H), 7.81(s, 2H), 7.91(d, 2H), 8.53(d, 2H), 9.07(s, 1H), 10.99(s, 0.7H) and 11.16(s, 0.3H) ppm; MS (ES) ⁺)418.2

All of the following compounds were prepared using procedures analogous to those described above for compounds I A-82.

Compound IA-2192-amino-N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]-2-methyl-propionamide 1H NMR (400.0MHz, DMSO) d 1.18(d, 6H), 1.21(s, 6H), 3.43-3.53(m, 1H), 7.80(brs, 2H), 7.88(d, 2H), 8.08(s, 1H), 8.54(d, 2H), 9.01(s, 1H), 10.49(br s, 1H) and 10.62(s, 1H) ppm; MS (ES)⁺)446.2

The compound IA-2722-amino-N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Propionamide 1H NMR (400.0MHz, DMSO) d 1.19(d, 6H), 1.30(d, 1.8H), 1.39(d, 1.2H), 3.46-3.53(m, 1H), 4.34(br s, 0.6H), 4.54(br s, 0.4H), 7.82(br s, 2H), 7.91(d, 2H), 8.50-8.55(m, 2H), 9.09(s, 1H), 11.06(br s, 0.6H) and 11.17(br s, 0.4H) ppm; MS (ES)⁺)432.2

Example 54A: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -N- (3-piperidinyl) -1, 3, 4-oxadiazol-2-amine (compound IA-199)

Synthetic route

Compound IA-199

Compound IA-199 was prepared using method IV-C, step 1-2, then using method IV-K, step 1, then using method IV-AAA, step 1.

Method IV-AAA

Step 1: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -N- (3-piperidinyl) -1, 3, 4-oxadiazol-2-amine

DIPEA (173.6. mu.L, 1.0mmol), methyl 3-aminopiperidine-1-carboxylate (99.7mg, 0.50mmol) and bromo (trispyrrolidin-1-yl) phosphonium hexafluorophosphate (340.6mg, 0.73mmol) were added to 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-3H-1, 3, 4-oxadiazol-2-one (120mg, 0.33mmol) in a mixture of DMF (600. mu.L) and DMSO (600. mu.L). The resulting mixture was stirred at room temperature for 4.5 h. The reaction mixture was diluted with EtOAc (5mL) and saturated aqueous sodium bicarbonate (5 mL). The aqueous layer was washed with EtOAc (3X 5mL) and MgSO₄The combined organic extracts were dried, filtered, and concentrated in vacuo. The residue was dissolved in methanol (1.2mL) and HCl (332. mu.L, 1.0mmol, 3M in methanol) and the resulting solution was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, the solid was triturated with acetonitrile and then further purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were passed through a bicarbonate column and lyophilized to give the title compound as a yellow solid (29.6mg, 20%); h NMR (400.0MHz, DMSO) d 1.19(d, 6H), 1.43-1.48(m, 2H), 1.64-1.67(m, 1H), 1.99-2.01(m, 1H), 2.40-2.46(m, 2H), 2.77-2.80(m, 1H), 3.10-3.14(m, 1H), 3.46-3.55(m, 2H), 7.80(br s, 1H), 7.95(d, 2H), 8.23(t, 2H), 8.27(s, 1H) and 8.89(s, 1H) ppm; MS (ES) ⁺)444.25

All of the following compounds were prepared using analogous methods as described above for compound IA-199.

The compound IA-97N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Propane-1, 3-diamine 1H NMR (400.0MHz, DMSO) d1.18(d, 7H), 1.67(t, 2H), 2.64(t, 2H), 3.00-3.01(m, 2H), 3.46-3.50(m, 1H), 6.75(br s, 1H), 7.80(br s, 1H), 7.95(d, 2H), 8.26(d, 2H) and 8.89(s, 1H) ppm; MS (ES)⁺)418.21

The compound IA-1093- [5- (4-amino-1-piperidinyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.19(d, 6H), 1.45-1.60(m, 2H), 1.94(s, 2H), 2.08(s, 1H), 3.17-3.25(m, 4H), 3.45(t, 2H), 4.00(s, 2H), 7.75(br s, 1H), 7.93(d, 2H), 8.32(d, 2H) and 8.93(s, 1H) ppm; MS (ES)⁺)444.21

Compound IA-1113- [5- (3-amino azetidin-1-yl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d1.18 (dd, 6H), 2.35(br s, 2H), 2.95(br s, 2H), 3.40-3.55(m, 1H), 3.85-4.01(m, 2H), 4.00-4.30(m, 2H), 7.75(br s, 1H), 7.94(d, 2H), 8.27(d, 2H) and 8.91(s, 1H) ppm; MS (ES) ⁺)416.2

The compound IA-1383- [5- [4- (aminomethyl) -1-piperidinyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.16-1.19(m, 6H), 1.20-1.40(m, 3H), 1.50-1.95(m, 3H), 2.08(s, 1H), 2.54(s, 1H), 2.85-3.35(m, 3H), 3.40-3.50(m, 1H), 3.95-4.10(m, 2H), 7.75(br s, 1H), 7.94(d, 2H), 8.31(d, 2H) and 8.92(s, 1H) ppm; MS (ES)⁺)458.21

The compound IA-1883- [5- (3-aminopyrrolidin-1-yl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.05(d, 6H), 1.95-2.05(m, 1H), 2.20-2.30(m, 1H), 2.95(t, 3H), 3.40-3.55(m, 2H), 3.60-3.70(m, 1H), 3.70-3.80(m, 2H), 3.80-3.90(m, 1H), 5.15(s, 1H), 7.80(d, 2H), 8.16(d, 2H) and 8.78(s, 1H) ppm；MS(ES⁺)430.27

The compound IA-2273- [5- [3- (aminomethyl) -1-piperidinyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine MS (ES)⁺)458.23

Compound I A-2063- [5- (3-amino-1-piperidinyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.19(d, 6H), 1.45-1.65(m, 1H), 1.75-1.90(m, 2H), 2.08(s, 1H), 2.75-3.20(m, 5H), 3.40-3.50(m, 1H), 3.75-3.95(m, 2H), 7.75(s, 2H), 7.94(d, 2H), 8.32(d, 2H) and 8.91(s, 1H) ppm; MS (ES) ⁺)444.21

Compounds IA-2395- (4-isopropylsulfonylphenyl) -3- (5-piperazin-1-yl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d1.18(d, 6H), 2.67(s, 1H), 2.98(s, 3H), 3.10(d, 2H), 3.40-3.50(m, 1H), 3.57-3.60(m, 4H), 7.75(br s, 1H), 7.93(d, 2H), 8.32(d, 2H) and 8.93(s, 1H) ppm; MS (ES)⁺)430.23

Compound IA-3185- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl vN- (4-piperidinyl) -1, 3, 4-oxadiazol-2-amine 1H NMR (400.0MHz, DMSO) d1.18(d, 6H), 1.35-1.45(m, 2H), 1.95-2.00(m, 2H), 2.95-3.00(m, 2H), 3.40-3.55(m, 2H), 7.95(d, 2H), 8.25-8.35(m, 3H) and 8.90(s, 1H) ppm; MS (ES)⁺)444.2

Example 55: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -N-pyrrolidin-3-yl-1, 3, 4-oxadiazole-2-carboxamide (Compound IA-114)

Synthetic route

Compounds IA-114

Compound IA-114 was prepared using method IV-C, step 1-2, followed by method IV-AAB, steps 1-3.

Process IV-AAB

Step 1: 2- (2- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carbonyl) hydrazino) -2-oxoglycolic acid ethyl ester

3-amino-6- (4-isopropylsulfonylphenyl) pyrazine-2-carboxylic acid hydrazide (2g, 5.963mmol) and Et3N (1.810g, 2.493mL, 17.89mmol) were dissolved in THF (128.0mL) and treated dropwise with ethyl 2-chloro-2-oxo-acetate (814.2mg, 666.3. mu.L, 5.963mmol) at 0 ℃. The reaction mixture was slowly warmed to room temperature and stirred for 1.5 h. The reaction mixture was filtered and the grey solid was washed with THF. The filtrate was evaporated to dryness and azeotroped with acetonitrile. The residue was then triturated with acetonitrile to give the product as a yellow solid (1.52g, 58%); 1H NMR (400MHZ, DMSO) d 1.19(m, 6H), 1.32(m, 3H), 3.34(m, 1H), 4.32(m, 2H), 7.88(m, 2H), 8.56(m, 2H), 9.07(s, 1H), 10.95(s, 1H) and 11.05(s, 1H) ppm; MS (ES) ⁺)436.32

Step 2: 5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazole-2-carboxylic acid ethyl ester

To a stirred solution of ethyl 2- (2- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carbonyl) hydrazino) -2-oxoacetate (1.1894g, 2.731mmol) in CH₂Cl₂To a solution in (23.78mL) was added triethylamine (552.7mg, 761.3. mu.L, 5.462mmol) followed by 4-methylbenzenesulfonyl chloride (520.7mg, 2.731mmol), and the resulting solution was stirred at room temperature for 3 h. By CH₂Cl₂The reaction mixture was diluted and washed with water (1 × 20mL), saturated aqueous sodium bicarbonate (1 × 20mL), and brine (1 × 20 mL). With MgSO₄The organic extract was dried, filtered and concentrated in vacuo. The residue was triturated with acetonitrile to give the product as a yellow solid (1.03g, 90%); 1H NMR (400MHz, DMSO) d 1.37(m, 6H), 1.54(m, 3H), 3.25(m, 1H), 4.64(m, 2H), 8.00(m, 2H), 8.20(m, 2H) and 8.83(s, 1H) ppm; MS (ES)⁺)418.19

And step 3: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -N-pyrrolidin-3-yl-1, 3, 4-oxadiazole-2-carboxamide

To 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]To a suspension of ethyl (e) -1, 3, 4-oxadiazole-2-carboxylate (100mg, 0.34mmol) in ethanol (2mL) was added methyl 3-aminopyrrolidine-1-carboxylate (49.1mg, 0.26mmol) and the resulting mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in CH ₂Cl₂(2.0mL), TFA (400. mu.L) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was passed through a bicarbonate column and the filtrate was concentrated in vacuo. The residue was passed through a Ts OH column, eluting the product with 2M ammonia in methanol (5 mL). Trituration of the solid from acetonitrile afforded the product as a yellow solid (44.94mg, 41%); 1H NMR (400.0MHz, DMSO) d1.19(d, 6H), 1.75(s, 1H), 2.00(d, 1H), 2.73-2.78(m, 2H), 2.94(s, 1H), 2.95(dd, 1H), 3.47(t, 1H), 4.40(br s, 1H), 7.85(br s, 2H), 7.98(d, 2H), 8.32-8.34(m, 2H), 9.09(s, 1H) and 9.46(d, 1H) ppm; MS (ES)⁺)458.22

All of the following compounds were prepared using analogous methods as described above for compounds IA-114.

Compound IA-79[5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]- (1, 4-diazepan-1-yl) methanone; MS (ES)⁺)472.3

The compound IA-81N- (2-aminocyclohexyl) -5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]1, 3, 4-oxadiazole-2-carboxamide 1H NMR (400.0MHz, DMSO) d1.19(d, 6H), 1.21-1.30(br s, 1H), 1.40-1.50(m, 1H), 1.65-1.75(m, 2H), 1.80-1.95(m, 2H), 2.75(br s, 2H), 3.45-3.50(m, 3H), 3.65(br s, 1H), 7.95(s, 2H), 8.45(s, 2H), 9.10(s, 1H) and 9.30(br s, 1H) ppm; MS (ES) ⁺)486.35

Compound IA-98[5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazole-2-yl]- (3-amino-1-piperidinyl) methanone 1H NMR (400.0MHz, DMSO) d 1.19(d, 6H), 1.34-1.38(m, 1H), 1.48-1.51(m, 1H), 1.76-1.92(m, 3H), 2.67-2.81(m, 2H), 3.17-3.29(m, 2H), 3.50-3.99(m, 1H), 4.09-4.10(m, 0.5H), 4.12-4.23(m, 0.5H), 4.24-4.30(m, 1H), 7.85(br s, 1H), 7.98(d, 2H), 8.32(dd, 2H), and 9.09(s, 1H) ppm; MS (ES)⁺)472.28

Compound IA-1135- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]1, 3, 4-oxadiazole-2-carboxylic acid butyl ester 1H NMR (400.0MHz, DMSO) d0.97(t, 3H), 1.19(d, 6H), 1.46(d, 2H), 1.75-1.78(m, 2H), 2.08(s, 1H), 3.47-3.55(m, 1H), 4.46(t, 2H), 7.75(br s, 1H), 7.99(d, 2H), 8.31(d, 2H) and 9.10(s, 1H) ppm; MS (ES)⁺)446.22

The compound IA-120 (3-aminoazetidin-1-yl) - [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Methanone 1HNMR (400.0MHz, DMSO) d 1.18-1.20(m, 6H), 2.50(br s, 1H), 2.55(s, 1H), 3.05(br s, 2H), 3.45-3.52(m, 1H), 3.76-3.80(m, 1H), 3.82-3.87(m, 1H), 4.22-4.26(m, 1H), 4.31-4.36(m, 1H), 4.76-4.79(m, 1H), 7.98(d, 2H), 8.32(d, 2H) and 9.09(s, 1H) ppm; MS (ES) ⁺)444.28

Compound IA-133[5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]- (3-aminopyrrolidin-1-yl) methanone 1H NMR (400.0MHz, DMSO) d 1.19(d, 6H), 1.65-1.80(m, 1H), 1.95-2.10(m, 1H), 3.45-3.50(m, 2H), 3.55-3.75(m, 3H), 3.95-4.10(m, 1H), 7.75(brs, 1H), 7.98(d, 2H), 8.32(d, 2H) and 9.09(s, 1H) ppm; MS (ES)⁺)458.37

Compound IA-2555- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-N- (3-Piperidylmethyl) -1, 3, 4-oxadiazole-2-carboxamide 1H NMR (400.0MHz, DMSO) d 1.05-1.10(m, 1H), 1.19(d, 6H), 1.25-1.35(m, 1H), 1.55-1.59(m, 1H), 1.73-1.75(m, 1H), 2.19-2.22(m, 1H), 2.33-2.40(m, 1H), 2.80-2.82(m, 1H), 2.91-2.94(m, 1H), 3.18(s, 1H), 3.18-3.21(m,2H) 3.47-3.50(m, 1H), 7.85(br s, 1H), 7.98(d, 2H), 8.33(d, 2H), 9.09(s, 1H) and 9.44-9.47(m, 1H) ppm; MS (ES)⁺)486.29

Example 56A: (2S) -N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] piperidine-2-carboxamide (Compound IA-211)

Synthetic route

Compound IA-211

Compound IA-211 was prepared using method IV-C, step 1-2, then using method IV-AY, step 1-2, then using method IV-AAC, step 1.

Method IV-AAC

Step 1: (2S) -N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] piperidine-2-carboxamide

Pd/C wet degussa (50mg,) was added to a stirred solution of benzyl (S) -2- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-ylcarbamoyl) piperidine-1-carboxylate (251mg, 0.25mmol) in MeOH (5mL)/EtOAc (5mL), and the reaction mixture was taken up in H₂In an atmosphere. The reaction was stirred at ambient temperature for 17 hours. Once the reaction was complete, the Pd was removed by filtration and the solvent was removed in vacuo. This material was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected and lyophilized to give the product as a yellow solid (56.4mg, 39%); 1H NMR (400.0MHz, DMSO) d 1.19 (d)6H), 1.38-1.49(m, 2H), 1.51-1.61(m, 1H), 1.80-1.83(m, 1H), 1.89-1.92(m, 1H), 2.09-2.11(m, 1H), 3.01(br s, 2H), 3.19-3.23(m, 1H), 3.47-3.51(m, 1H), 4.13(d, 1H), 4.31(br s, 1H), 7.81(s, 2H), 7.91(d, 2H), 8.52(d, 2H), 9.06(s, 1H) and 11.04(br s, 1H) ppm; MS (ES) ⁺)472.3

All of the following compounds were prepared using analogous methods as described above for compounds IA-211.

The compound IA-160(1R, 4S, 6S) -N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]-5-azabicyclo [2.2.1]Heptane-6-carboxamide 1H NMR (400.0MHz, DMSO) d 1.18(d, 6H), 1.34-1.45(m, 2H), 1.55-1.76(m, 4H), 2.68(br d, 1H), 3.44-3.52(m, 1H), 3.64(s, 0.6H), 3.76(s, 0.4H), 4.25(s, 0.6H), 4.33(s, 0.4H), 7.88(d, 1.2H), 7.90(br s, 2H), 7.92(d, 0.8H), 8.31(d, 0.8H), 8.53(d, 1.2H), 9.00(d, 1H), 10.43(s, 0.4H) and 10.86(s, 0.6H) ppm; MS (ES)⁺)484.3

The compound IA-217(2S) -N- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Pyrrolidine-2-carboxamide 1H NMR (400.0MHz, DMSO) d 1.18(d, 6H), 1.67-1.72(m, 1H), 2.04-2.21(m, 2H), 3.00(br s, 2H), 3.35-3.41(m, 1H), 3.45-3.59(m, 3H), 4.28-4.34(m, 1H), 7.82(br s, 2H), 7.88-7.92(m, 2H), 8.44-8.53(m, 2H), 9.00-9.01(2 x s, 1H) and 10.87(s, 1H) ppm; MS (ES)⁺)458.3

Example 57A: 5- (4-Isopropylsulfonylphenyl) -3- [3- [4- (methylaminomethyl) phenyl ] isoxazol-5-yl ] pyrazin-2-amine (Compound IIA-7)

Synthetic route

Compound IAA-7

Compound IIA-7 was prepared using method IV-F, step 1-2, followed by method IV-AAD, steps 1-4.

Process IV-AAD

Step 1: n- (3-ethynyl-5- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

Reacting N- [ 5-bromo-3- (2-trimethylsilylethynyl) pyrazin-2-yl]-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (3g, 6.377mmol) and (4-isopropylsulfonylphenyl) boronic acid (1.491g, 6.536mmol) were dissolved in MeCN (60.00mL) and then treated with water (12.00mL) and K₃PO₄(2.706g, 12.75mmol) and then degassed/purged with nitrogen (x5 cycles). With Pd [ P (tBu)₃]₂(162.9mg, 0.3188mmol) and recharged with Vac/Nitrogen x 5. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quickly poured into a mixture of ethyl acetate (500mL), water (90mL) and 1% sodium metabisulfite at 4 deg.C, shaken well, the layers separated, and MgSO₄The organic fraction was dried, filtered and the filtrate was treated with 3-mercaptopropylethylthio/silica (0.8mmol/g) (1g) to make it pre-adsorbed on silica gel and then purified by silica gel column chromatography eluting with 30-40% EtOAc/petroleum ether. The product fractions were combined and concentrated in vacuo to afford the product as a yellow/brown viscous oil. Triturate with petroleum ether and add some ether and a small amount of dichloromethane. Standing at room temperature for 30min to form light yellow crystals, which were isolated by filtration to give the product as a light yellow solid (1.95g, 61%); 1H NMR (400MHz, DMSO) d 1.20(m, 6H), 1.39(s, 18H), 3.50(m, 1H), 5.01(s, 1H), 8.03(m, 2H), 8.46(m, 2H) and 9.37(s, 1H) ppm.

Step 2: n- [5- (4- (isopropylsulfonyl) phenyl) -3- (3- (4-methyl) phenylisoxazol-5-yl) pyrazin-2-yl ] -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

N-tert-Butoxycarbonyl-N- [ 3-ethynyl-5- (4-isopropylsulfonylphenyl) pyrazin-2-yl is added within 10min at room temperature]Carbamic acid tert-butyl ester (6.8g, 13.56 mm)ol) and N-hydroxy-4-methyl-aminobenzylidene chloride (2.706g, 13.56mmol) in THF (141.6mL) TEA (1.646g, 2.267mL, 16.27mmol) was added dropwise. The mixture was stirred at room temperature overnight and then at 60 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure and dissolved in CH₂Cl₂(30mL), with brine (1X 50mL) and NaHCO₃Aqueous (1 × 50mL) wash. With MgSO₄The organic extract was dried and poured gently onto a silica gel column (300 ml). Elution with 20% EtOAc/petroleum ether afforded the product (7.1g, 82%); 1H NMR (400Mhz, DMSO) d1.21(m, 6H), 1.33(s, 18H), 3.34(s, 3H), 3.55(m, 1H), 7.39(m, 2H), 7.92(m, 2H), 8.01(s, 1H), 8.07(m, 2H), 8.66(m, 2H 0 and 9.51(s, 1H) ppm

And step 3: n- [5- (4- (isopropylsulfonyl) phenyl) -3- (3- (4-bromomethyl) phenylisoxazol-5-yl) pyrazin-2-yl ] -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

Tert-butyl N-tert-butoxycarbonyl-N- [5- (4-isopropylsulfonylphenyl) -3- [3- (p-tolyl) isoxazol-5-yl ] pyrazin-2-yl ] carbamate (1g, 1.575mmol) was dissolved in ethyl acetate (10mL) and NBS (364.5mg, 2.048mmol) and AI BN (25.86mg, 0.1575mmol) were added. The resulting mixture was heated to 75 ℃ and placed under a light for 1 h. After this time, the reaction mixture was concentrated in vacuo to give an oil, which was used in the next step without further purification.

And 4, step 4: 5- (4-isopropylsulfonylphenyl) -3- [3- [4- (methylaminomethyl) phenyl ] isoxazol-5-yl ] pyrazin-2-amine

Reacting N- [3- [3- [4- (bromomethyl) phenyl]Isoxazol-5-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-tert-Butoxycarbonyl-carbamic acid tert-butyl ester (60mg, 0.08408mmol) was added to a solution of methylamine in ethanol (3mL) (791.3mg, 8.408 mmol). The reaction mixture was stirred at room temperature for 1h, then the solvent was removed in vacuo to give an oil. Redissolving the oil in CH₂Cl₂(10ml) and concentrated to an oil to remove any excess amine. The oil was dissolved in CH₂Cl₂(5mL), TFA (479.4mg, 323.9. mu.L, 4.204 m) was addedmol). The mixture was stirred at room temperature for 1h and the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were passed through a bicarbonate column and lyophilized to give the title compound as a yellow solid (13.6g, 28% yield); 1H NMR (400MHz, DMSO) d 1.22(d, 6H), 2.6-2.65(m, 3H), 3.5-3.6(m, 1H), 4.2-4.25(m, 2H), 7.2-73(br s, 2H), 7.65(d, 2H), 7.82(s, 1H), 7.85(d, 2H), 8.1(d, 2H), 8.4(d, 2H), 8.85(br s, 2H) and 8.92(s, 1H) ppm; MS (ES) ⁺)464.4

All of the following compounds were prepared using procedures analogous to those described above for compound IIA-7.

Compounds IIA-42- (2- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) isoxazol-3-yl) benzylamino) ethoxy) ethanol 1H NMR (400MHz, DMSO) d 1.22(d, 6H), 3.2-3.25(m, 2H), 3.5-3.6(m, 2H), 3.6-3.63(m, 2H), 3.5-3.8(m, 2H), 4.3-4.35(m, 2H), 4.75(br s, 1H), 7.2-73(br s, 2H), 7.65(d, 2H), 7.82(s, 1H), 7.95(d, 2H), 8.1(d, 2H), 8.4(d, 2H) and 8.9-9.05(m, 3H) ppm; MS (ES)⁺)538.4

Compound IIA-53- [3- [4- (aminomethyl) phenyl]Isoxazol-5-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d 1.22(d, 6H), 3.5-3.6(m, 1H), 4.2-4.25(m, 2H), 7.2-73(br s, 2H), 7.65(d, 2H), 7.82(s, 1H), 7.95(d, 2H), 8.1(d, 2H), 8.4(d, 2H), 8.2(br, 2H) and 8.97(s, 1H) ppm; MS (ES)⁺)450.4

The compounds IIA-65- (4- (isopropylsulfonyl) phenyl) -3- (3- (4- ((propylamino) methyl) phenyl) isoxazol-5-yl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d0.95(t, 3H), 1.22(d, 6H), 1.6-1.7(m, 2H), 2.9-3.0(m, 2H), 3.5-3.6(m, 1H), 4.2-4.25(m, 2H), 7.2-73(br s, 2H) ) 7.65(d, 2H), 7.82(s, 1H), 7.95(d, 2H), 8.1(d, 2H), 8.4(d, 2H), 8.8(br s, 2H) and 8.97(s, 1H) ppm; MS (ES)⁺)492.4

Compound IA-83- [3- [4- [ (isopropylamino) methyl ] methyl]Phenyl radical]Isoxazol-5-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.2(d, 6H), 1.3(d, 6H), 3.5-3.6(m, 1H), 4.2-4.25(m, 2H), 7.2-73(br s, 2H), 7.65(d, 2H), 7.82(s, 1H), 7.95(d, 2H), 8.1(d, 2H), 8.4(d, 2H), 8.7(br s, 2H) and 8.95(s, 1H) ppm; MS (ES)⁺)492.4

Compounds I IA-92- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) isoxazol-3-yl) benzylamino) ethanol 1H NMR (400MHz, DMSO) d1.22(d, 6H), 3.0-3.1(m, 2H), 3.5-3.6(m, 1H), 3.65-3.7(m, 2H), 4.2-4.25(m, 2H), 5.3(br s, 1H), 7.2-73(br s, 2H), 7.65(d, 2H), 7.82(s, 1H), 7.95(d, 2H), 8.1(d, 2H), 8.4(d, 2H), 8.8(br s, 2H) and 8.87(s, 1H) ppm; MS (ES)⁺)494.3

Compound IIA-103- [3- [4- (ethylaminomethyl) phenyl]Isoxazol-5-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400MHz, DMSO) d1.22(d, 6H), 1.25(t, 3H), 3.0-3.1(m, 2H), 3.5-3.6(m, 1H), 4.2-4.25(m, 2H), 7.2-73(br s, 2H), 7.65(d, 2H), 7.82(s, 1H), 7.95(d, 2H), 8.1(d, 2H), 8.4(d, 2H), 8.8(br s, 2H) and 8.97(s, 1H) ppm; MS (ES) ⁺)478.4

Compounds IIA-111- (4- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) isoxazol-3-yl) benzylamino) propan-2-ol 1H NMR (400MHz, DMSO) d 1.05(d, 3H), 1.22(d, 6H), 3.0-3.1(m, 2H), 2.65-2.7(m, 1H), 2.8-2.85(m, 1H), 3.5-3.6(m, 1H), 3.8-3.85(m, 1H), 4.2-4.25(m, 2H), 5.3-5.33(m, 1H), 7.2(br s, 2H), 7.65(d, 2H), 7.82(s, 1H), 7.85(d, 2H), 8.02(d, 2H), 8.35(d, 2H), 8.8.87 (br s, 8.87H), 1H) ppm; MS (ES)⁺)508.4

Example 58A: 5- (4-Isopropylsulfonylphenyl) -3- [5- [4- [1- (methylamino) ethyl ] phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine (compound IA-212)

Synthetic route

Compound IA-212

Compound IA-212 was prepared using method IV-C, step 1-2, then using method IV-R, step 1, then using method IV-AAE, step 1.

Process IV-AAE

Step 1: 5- (4-Isopropylsulfonylphenyl) -3- [5- [4- [1- (methylamino) ethyl ] phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine

1- [4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Ethanone (130mg, 0.2805mmol), methylamine hydrochloride (37.88mg, 0.5610mmol), Ti (OiPr) ₄A mixture of (159.4mg, 165.5. mu.L, 0.5610mmol) and triethylamine (56.77mg, 78.20. mu.L, 0.5610mmol) was stirred at room temperature in ethanol (2mL) under a nitrogen atmosphere overnight. The reaction mixture was treated with sodium borohydride (15.92mg, 16.85 μ L, 0.4208mmol), stirred at room temperature over 1 weekend, and then quenched with aqueous ammonia (1mL of concentrated 4mL aqueous solution). The mixture was extracted with dichloromethane and MgSO₄The organic extracts were dried and concentrated in vacuo. The residue was purified by preparative HPLC [ Waters sunfire c18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were passed through a bicarbonate column and concentrated in vacuo. Trituration of the solid with acetonitrile afforded the product as a pale yellow solid (27.0mg, 22%); 1H NMR (400MHz, DMSO) d 1.20(d, 6H), 1.28(d, 3H), 4.48(m,1H) 3.69(q, 1H), 7.72(d, 2H), 7.97(d, 2H), 7.98(vbr s, 2H), 8.12(d, 2H) and 9.07(s, 1H) ppm; MS (ES)⁺)479.3

Example 59A: 5- (4-Isopropylsulfonylphenyl) -3- [5- [ 2-methyl-4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine (Compound IA-166)

Synthetic route

Compound IA-166

Compound IA-166 was prepared using method IV-B, steps 1-4, followed by method IV-AAF, step 1.

Process IV-AAF

Step 1: 5- (4-Isopropylsulfonylphenyl) -3- [5- [ 2-methyl-4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine

To N- [ [4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]-3-methyl-phenyl]Methyl radical]-N-methyl-carbamic acid tert-butyl ester (120mg, 0.2074mmol) in CH₂Cl₂To a solution in (10mL) was added TFA (709.5mg, 479.4. mu.L, 6.222mmol) and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and redissolved in CH₂Cl₂(20ml) and concentrated. The residue was purified by preparative HPLC [ Waters sunfire c18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Product fractions were combined and lyophilized to give the product as a yellow solid (48.0mg, 39%); 1H NMR (400MHz, DMSO) d 1.2(d, 6H), 2.6(s, 3H), 2.75(s, 3H), 3.4-3.5(m, 1H),4.25(s, 2H), 7.7(d, 1H), 7.72(s, 1H), 8.0-8.1(m, 3H), 8.2(d, 1H), 8.4(d, 2H), 8.8(br s, 2H) and 9.2(s, 1H) ppm; MS (ES) ⁺)479.4

Example 60A: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazole-2-carboxylic acid (Compound IA-128)

Synthetic route

Compound IA-128

Compound IA-128 was prepared using method IV-C, step 1-2, then using method IV-AAB, step 1-2, then using method IV-AAG, step 1.

Process IV-AAG

Step 1: 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazole-2-carboxylic acid

Reacting 5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]A solution of ethyl-1, 3, 4-oxadiazole-2-carboxylate (50mg, 0.1198mmol) in NaOH (59.90. mu.L, 1M, 0.05990mmol) was stirred at room temperature for 1 h. Water (0.5mL) was added and the reaction mixture was stirred at room temperature for 5min, then filtered. The resulting yellow solid was dried in vacuo to afford the product (30.93mg, 62%); 1H NMR (400MHz, DMSO) d 1.19(d, 6H), 3.40-3.49(m, 1H), 7.90(br s, 2H), 7.96(d, 2H), 8.32(d, 2H) and 9.00(s, 1H) ppm; MS (ES)⁺)390.13

Example 61A: 3- (5-ethynyl-1, 3, 4-oxadiazol-2-yl) -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound I A-258)

Synthetic route

Compound IA-258

Compound IA-258 was prepared using method IV-C, step 1-2, followed by method IV-AAH, step 1.

Process IV-AAH

Step 1: 3- (5-ethynyl-1, 3, 4-oxadiazol-2-yl) -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine

Dibromo (triphenyl) phosphane (1.208g, 2.862mmol) was added to a suspension of 3-trimethylsilylpropan-2-ynoic acid (84.8mg, 0.60mmol) and 3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxylic acid hydrazide (200mg, 0.60mmol) in acetonitrile (3.000mL) at room temperature, and the resulting solution was stirred for 30 min. DIPEA (385.4mg, 519.4. mu.L, 2.982mmol) was then added and a precipitate formed rapidly. The resulting mixture was stirred at room temperature for 1h, then filtered. The reaction mixture was concentrated in vacuo, the residue dissolved in methanol (5mL), potassium carbonate (131.9mg, 0.9541mmol) was added, and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (5mL) and water (5mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2X 5mL) over MgSO₄Drying and vacuum concentrating. This material was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were freeze-dried to give the product as a yellow solid (56.1mg, 27% yield); 1H NMR (400MHz, DMSO) d 1.18(m, 6H), 3.44(m, 1H), 5.48(s, 1H), 7.96(m, 2H), 8.32(m, 2H) and 9.08(s, 1H) ppm; MS (ES) ⁺)370.14

Example 62A: 2- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] acetic acid (Compound IA-78)

Synthetic route

Compounds IA-78

Compound IA-78 was prepared using method IV-C, step 1-2, then using method IV-X, step 1-2, then using method IV-AAI, step 1.

Process IV-AAI

Step 1: 2- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] acetic acid

Add TFA (500. mu.L, 6.490mmol) to acetic acid 2- (5- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) ester (45mg, 0.083mmol) in CH₂Cl₂(5mL) the reaction was stirred at ambient temperature for 18 h. The solvent was removed in vacuo and the residue taken up with CH₂Cl₂(2X 5mL) was azeotroped with diethyl ether (2X 5mL) and the material was purified by preparative HPLC [ Waters Sunfire C18, 10. mu.M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected, lyophilized to give the title compound as a yellow solid (16.7mg, 49%); 1H NMR (400MHz, DMSO) d 1.19(d, 6H), 3.45(m, 1H), 4.27(s, 2H), 7.85(br s, 2H), 7.96(d, 2H), 8.30(d, 2H), 9.04(s, 1H) and 13.30(s, 1H) ppm; MS (ES) ⁺)404.2

Example 63A: 5- (4-Isopropylsulfonylphenyl) -3- [5- [ 2-methoxy-4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine (Compound IA-171)

Synthetic route

Compounds IA-171

Compounds I A-171 were prepared using method IV-B, steps 1-4, followed by method IV-AAJ, steps 1-3.

Process IV-AAJ

Step 1: di-tert-butyl (5- (4- (isopropylsulfonyl) phenyl) -3- (5- (2-methoxy-4-methylphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) iminodicarbonate

Di-tert-butyl dicarbonate (703.2mg, 740.2. mu.L, 3.222mmol) and DMAP (7.872mg, 0.06444mmol) are added to 5- (4-isopropylsulfonylphenyl) -3- [5- (2-methoxy-4-methyl-phenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazine-2-amine (300mg, 0.6444mmol) in a suspension in a mixture of acetonitrile (10mL) and THF (10 mL). The reaction mixture was stirred at room temperature for 2h, then heated at 50 ℃ for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 20% diethyl ether/petroleum ether. Product fractions were combined and concentrated in vacuo to afford the product (253mg, 59%); MS (ES)⁺)666.31

Step 2: di-tert-butyl (5- (4- (isopropylsulfonyl) phenyl) -3- (5- (2-methoxy-4-methylaminomethylphenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-yl) iminodicarbonate

NBS (120.3mg, 0.6760mmol) and AI BN (17.08mg, 0.1040mmol) were added to N-tert-butoxycarbonyl-N- [5- (4-isopropylsulfonylphenyl) -3- [5- (2-methoxy-4-methyl-phenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]Tert-butyl carbamate (346.2mg, 0.5200mmol) in ethyl acetate (40 mL). The resulting mixture was heated to reflux for 2h while under light. The reaction mixture was cooled to room temperature and added directly at room temperatureTo a solution of methylamine in ethanol (2.447g, 26.00 mmol). The reaction mixture was stirred at room temperature for 30min, then concentrated in vacuo to give an oil. Redissolving the oil in CH₂Cl₂(50ml) and concentrated in vacuo to remove any excess amine. The product was purified by silica gel column chromatography with 5% MeOH/CH₂Cl₂And (4) eluting. The product fractions were combined and concentrated in vacuo to give the product as a yellow oil (148mg, 41%)

And step 3: 5- (4-Isopropylsulfonylphenyl) -3- [5- [ 2-methoxy-4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine

TFA (393.7mg, 266.0. mu.L, 3.453mmol) was added to N-tert-butoxycarbonyl-N- [5- (4-isopropylsulfonylphenyl) -3- [5- [ 2-methoxy-4- (methylaminomethyl) phenyl ] phenyl ]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]Carbamic acid tert-butyl ester (80mg, 0.1151mmol) CH₂Cl₂(10 mL). The resulting mixture was stirred at room temperature for 1h, then concentrated in vacuo to give an oil. Redissolving the oil in CH₂Cl₂(10ml) and evaporated to dryness. The residue was purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. Fractions were collected, lyophilized to give the title compound as a yellow solid (27.1mg, 39%); 1H NMR (400MHz, DMSO) d 1.3(d, 6H), 2.65-2.7(m, 3H), 3.4-3.5(m, 1H), 4.0(s, 3H), 4.25-4.3(m, 2H), 7.25(d, 1H), 7.5(s, 1H), 8.0(d, 2H), 8.1(d, 1H), 8.38(d, 2H), 8.92(br s, 2H) and 9.1(s, 1H) ppm; MS (ES)⁺)495.3

Example 64A: 5- (2-fluoro-4-isopropylsulfonyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine (compound IA-292)

Synthetic route

Compound IA-292

Compound IA-292 was prepared using method IV-AAK, steps 1-5.

Process IV-AAK

Step 1: 4- (2- (3-amino-6-bromopyrazine-2-carbonyl) hydrazinecarbonyl) benzyl (methyl) carbamic acid tert-butyl ester

To N- [ [4- (hydrazinecarbonyl) phenyl]Methyl radical]To a solution of tert-butyl-N-methyl-carbamate (1g, 3.580mmol) in DMF (7.769mL) and 2-amino-5-bromo-pyridine-3-carboxylic acid (776.9mg, 3.580mmol) was added triethylamine (724.5mg, 997.9. mu.L, 7.160mmol) followed by TBTU (1.724g, 5.370 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with ethyl acetate (20mL) and water (20mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20mL), the combined organic extracts were washed with saturated aqueous sodium bicarbonate (1 × 20mL), brine (1 × 20mL), and MgSO₄Drying and vacuum concentrating. The residue is reacted with CH₂Cl₂Trituration together afforded the product as a white solid (1.71g, 58% yield); 1H NMR (400.0MHz, DMSO) d 1.39-1.45(m, 9H), 2.80(s, 3H), 4.45(s, 2H), 4.45(s, 2H), 7.28(s, 2H), 7.35(d, 2H), 7.90(d, 2H), 8.20(d, 2H), 8.24(d, 1H), 10.50(s, 1H) and 10.54(s, 1H) ppm; MS (ES)⁺)480.16

Step 2: 4- ((5- (3-amino-6-bromopyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) methyl) benzyl (methyl) carbamic acid tert-butyl ester

To N- [ [4- [ [ (2-amino-5-bromo-pyridine-3-carbonyl) amino group at 0 deg.C]Carbamoyl radical]Phenyl radical]Methyl radical ]-N-methyl-carbamic acid tert-butyl ester (992.3mg, 2.074mmol) in dry MeCN (14.88mL) DIPEA (804.2mg, 1.084mL, 6.222mmol) was added followed by stepwise addition of dibromo (triphenyl) phosphane (1.185g, 2).696mmol), the resulting mixture was stirred at 0 ℃ for 1h, then at room temperature overnight. The reaction mixture was evaporated to dryness and then purified by column chromatography using ISCO column comapnion system (40g column, 0-20% EtOAc/petroleum ether. the product fractions were combined and concentrated in vacuo to give the product as a white solid (681.6mg, 63% yield); 1H NMR (400.0MHZ, DMSO) d1.39-1.46(d, 9H, 4.48(d, 2H), 7.46(d, 2H), 8.22(d, 2H), 8.32(d, 1H) and 8.49(d, 1H) ppm; MS (ES) in ppm⁺)462.12

And step 3: n- [ [4- [5- [3- [ bis (tert-butoxycarbonyl) amino ] -6-bromo-pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] phenyl ] methyl ] -N-methyl-carbamic acid tert-butyl ester

Di-tert-butyl dicarbonate (1.306g, 1.375mL, 5.984mmol) is added to N- [ [4- [5- (3-amino-6-bromo-pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl ] -N- [ [4- [5- (3-amino-6-bromo-pyrazin-2-yl ] at room temperature]Phenyl radical]Methyl radical]-N-methyl-carbamic acid tert-butyl ester (885mg, 1.496mmol) and DMAP (18.28mg, 0.1496 mmol) in anhydrous THF (20 mL). The reaction was stirred at room temperature for 18 h. DIPEA (580.0mg, 781.7. mu.L, 4.488mmol) and di-tert-butyl dicarbonate (1.306g, 1.375mL, 5.984mmol) were added and the reaction was stirred at room temperature for an additional 2 h. Will CH ₂Cl₂(10mL) was added to aid dissolution and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (ISCOCompanion, 40g column, eluting with 0-50% Et OAc/petroleum ether, loaded with CH₂Cl₂) To give the product as a yellow-white solid (810mg, 82% yield); 1H NMR (400.0MHz, DMSO) d 1.26(s, 18H), 1.37-1.45(m, 9H), 2.85(brs, 3H), 4.49(s, 2H), 7.50(d, 2H), 8.15(d, 2H) and 8.95(d, 2H) ppm

And 4, step 4: 4- (5- (3-bis (tert-butyloxycarbonyl) amino-6- (2-fluoro-4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) benzyl (methyl) carbamic acid tert-butyl ester

Reacting N- [ [4- [5- [3- [ bis (tert-butyloxycarbonyl) amino group]-6-bromo-pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]Methyl radical]-N-methyl-carbamic acid tert-butyl ester (100mg, 0.1512mmol) in DMF (1mL),2- (2-fluoro-4-isopropylsulfonyl-phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (74.44mg, 0.2268mmol) and Pd (PPh) were added₃)₂Cl₂(6.254mg, 0.01512 mmol). Adding Na₂CO₃(226.8. mu.L, 2M, 0.4536mmol), the reaction was heated at 80 ℃ for 1h in a sealed tube under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc (5mL) and water (5mL), and the aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic extracts were washed with water (3X 5mL), brine (2X 5mL), and MgSO ₄Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (ISCO company, 24g column, eluting with 0-50% EtOAc in petroleum ether, loaded with CH)₂Cl₂) The product was obtained as a yellow-white solid and used without further purification (114.4mg, 96% yield)

And 5: 5- (2-fluoro-4-isopropylsulfonyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl ] -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine

TFA (1mL, 12.98mmol) was added to tert-butyl 4- (5- (3-bis (tert-butoxycarbonyl) amino-6- (2-fluoro-4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) -1, 3, 4-oxadiazol-2-yl) benzyl (methyl) carbamate (114mg, 0.1456mmol) in CH₂Cl₂(5 mL). The reaction was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue taken up with CH₂Cl₂(x 2) and diethyl ether (x 2) are azeotroped together. This material was purified by preparative HPLC [ Waters sunfire c18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were collected, passed through a sodium bicarbonate column, and lyophilized to give the title compound as a yellow solid (43.5mg, 62% yield); 1H NMR (400.0MHz, DMSO) d 1.23(d, 6H), 2.29(s, 3H), 3.58(m, 1H), 3.76(s, 2H), 7.60(d, 2H), 7.88(d, 2H), 8.00(br s, 2H), 8.10(d, 2H), 8.32(t, 1H) and 8.80(s, 1H) ppm; MS (ES) ⁺)483.3

All of the following compounds were prepared using procedures analogous to those described above for compound IA-292. In addition, all of the following compounds P1-P72, P146 and P149 can also be prepared using a method analogous to method AAK.

Compound IA-2905- [ 4-isopropylsulfonyl-3- (trifluoromethoxy) phenyl]-3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.24(d, 6H), 2.61(s, 3H), 3.53(sept, 1H), 4.24(s, 2H), 7.76(d, 2H), 8.08(d, 1H), 8.19(d, 2H), 8.35(s, 1H), 8.41(dd, 1H) and 9.17(s, 1H) ppm; MS (ES)⁺)549.2

Compound IA-2935- (4-isopropylsulfonyl-2-methyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.22(d, 6H), 2.28(s, 3H), 2.58(s, 3H), 3.48(d, 1H), 3.74(s, 2H), 7.58(d, 2H), 7.81-7.85(m, 4H), 8.05(d, J ═ 8.2Hz, 2H) and 8.60(s, 1H) ppm; MS (ES)⁺)479.3

The compound IA-2945- (4- (cyclopentylsulfonyl) phenyl) -3- (5- (4- ((methylamino) methyl) phenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

Compound IA-2955- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl ]Pyrazin-2-yl radicals]-2-isopropylsulfonyl-benzonitrile 1HNMR (400.0MHz, DMSO) d 1.28(d, 6H), 2.30(s, 3H), 3.63(m, 1H), 3.77(s, 2H), 7.62(d, 2H), 8.13(d, 2H), 8.22(d, 1H), 8.71(dd, 1H), 8.87(s, 1H) and 9.19(s, 1H) ppm; MS (ES)⁺)490.3

The compound IA-2983- (5- (4- ((methylamino) methyl) phenyl) -1, 3, 4-oxadiazol-2-yl) -5- (4- (1-methylpyrrolidin-3-ylsulfonyl) phenyl) pyrazin-2-amine

Compound IA-3005- (5-isopropylsulfonyl-2-pyridyl) -3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.23(d, 6H), 2.64(s, 3H), 3.59(m, 1H), 4.29(s, 2H),7.77(d, 2H), 8.28(d, 2H), 8.37-8.39(m, 1H), 8.56(d, 1H), 8.87(br s, 2H), 9.05(s, 1H) and 9.30(s, 1H) ppm; MS (ES)⁺)466.2

The compound IA-3035- (6-isopropylsulfonyl-3-pyridyl) -3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.24(d, 6H), 2.31(s, 3H), 3.76(m, 1H), 3.78(s, 2H), 7.62(d, 2H), 7.91(br s, 2H), 8.14-8.20(m, 3H), 8.81(dd, 1H), 9.15(s, 1H) and 9.54(d, 1H) ppm; MS (ES)⁺)466.2

The compound IA-3055- (3-chloro-4-isopropylsulfonyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl ]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.24(d, 6H), 2.30(s, 3H), 3.77(s, 2H), 3.79(m, 1H), 7.62(d, 2H), 8.11-8.14(m, 3H), 8.38(dd, 1H), 8.44(d, 1H) and 9.12(s, 1H) ppm; MS (ES)⁺)499.3

The compound IA-3125- (4-isopropylsulfonyl-3-methyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.20(d, 6H), 2.33(s, 3H), 2.74(s, 3H), 3.50(m, 1H), 3.82(s, 2H), 7.64(d, 2H), 7.96-7.98(m, 1H), 8.14(d, 2H), 8.20-8.23(m, 2H) and 9.06(s, 1H) ppm; MS (ES)⁺)479.3

Compound IA-3145- (3-fluoro-4-isopropylsulfonyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.25(d, 6H), 2.30(s, 3H), 3.76(s, 1H), 3.77(s, 2H), 7.62(d, 2H), 7.93-7.97(m, 1H), 8.13(d, 2H), 8.24(s, 1H), 8.24(dd, 1H) and 9.10(s, 1H) ppm; MS (ES)⁺)483.2

Compound IA-3165- (2-chloro-4-isopropylsulfonyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.24(d, 6H), 2.28(s, 3H), 3.63(t, 1H), 3.74(s, 2H), 7.58(d, 2H), 7.99-8.07(m, 5H) and 8.71(s, 1H) ppm; MS (ES) ⁺)499.2

Compound IA-3225- [2- (difluoromethyl) -4-isopropylsulfonyl-phenyl]-3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.23(d, 6H), 2.28(s, 3H), 3.55-3.65(m, 1H), 3.75(s, 2H), 7.59-7.62(m, 3H), 8.06(d, 2H), 8.16(s, 2H), 8.20(s, 1H) and 8.80(s, 1H) ppm; MS (ES)⁺)515.3

Compound IA-3265- (3-ethyl-4-isopropylsulfonyl-phenyl) -3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.21(d, 6H), 1.34(t, 3H), 2.68(t, 3H), 3.09(m, 2H), 3.45(m, 1H), 4.29(s, 2H), 7.77(d, 2H), 7.97(d, 1H), 8.21-8.27(m, 4H), 8.88(s, 2H) and 9.11(s, 1H) ppm; MS (ES)⁺)493.3

Compound IA-3312- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-5-isopropylsulfonyl-benzonitrile 1HNMR (400.0MHz, DMSO) d 1.23(d, 6H), 2.29(s, 3H), 3.66(s, 1H), 3.75(s, 2H), 7.60(d, 2H), 8.13(d, 2H), 8.24(m, 1H), 8.38-8.42(m, 2H) and 9.00(s, 1H) ppm; MS (ES)⁺)490.1

Example 65A: 5- (4-Isopropylsulfonylphenyl) -3- [3- [ 2-methyl-4- (methylaminomethyl) phenyl ] isoxazol-5-yl ] pyrazin-2-amine (Compound IIA-12)

Synthetic route

Compounds IA-12

Compound IIA-12 was prepared using method IV-F step 1-2, then using method IV-AAD step 1-2, then using method IV-AAL step 1.

Process IV-AAL

Step 1: 5- (4-isopropylsulfonylphenyl) -3- [3- [ 2-methyl-4- (methylaminomethyl) phenyl ] isoxazol-5-yl ] pyrazin-2-amine

TFA (556.9mg, 376.3. mu.L, 4.884mmol) was added to N- [ [4- [5- [3- [ bis (tert-butoxycarbonyl) amino group]-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]Isoxazol-3-yl]-3-methyl-phenyl]Methyl radical]To a solution of tert-butyl (190mg, 0.2442mmol) N-methyl-carbamate in dichloromethane (4.750mL) the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue dissolved in methanol (2mL) and dichloromethane (1mL), the product was eluted through an SCX column with 2M ammonia in methanol and concentrated in vacuo. The filtrate was then purified by reverse phase preparative HPLC [ waters sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were collected and lyophilized to give the product as a yellow solid (96.4mg, 69% yield); 1HNMR (400.0MHz, DMSO) d 1.18(d, 6H), 2.61(s, 3H), 2.62(m, 3H), 3.48(m, 1H), 4.20(m, 2H), 7.24(br s, 2H), 7.48-7.52(m, 2H), 7.63(s, 1H), 7.84(m, 1H), 7.93(m, 2H), 8.37(m, 2H), 8.81(br s, 2H) and 8.97(s, 1H) ppm; MS (ES) ⁺)478.3

All of the following compounds were prepared using procedures analogous to those described above for compounds IIA-12.

Compound IIA-133- [3- [ 3-chloro-4- (methylaminomethyl) phenyl]Isoxazol-5-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.19(m, 6H), 2.71(s, 3H), 3.48(m, 1H), 4.37(s, 2H), 7.24(brs, 2H), 7.79(m, 1H), 7.95(m, 2H), 8.12(m, 1H), 8.25(m, 1H), 8.38(m, 2H) and 8.98(br s, 2H) ppm; MS (ES)⁺)498.25

Compound IIA-143- [3- [ 2-fluoro-4- (methylaminomethyl) phenyl]Isoxazol-5-yl]-5- (4-Isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.18(m, 6H), 2.63(m, 3H), 3.47(m, 1H), 4.26(m, 2H), 7.26(brs, 2H), 7.51(m, 1H), 7.60(m, 1H), 7.65(m, 1H), 7.94(m, 2H), 8.13(t, 1H), 8.36(m, 2H), 8.88(br s, 2H) and 8.98(s, 1H) ppm; MS (ES)⁺)482.0

Compound IIA-153- [3- [ 2-chloro-4- (methylaminomethyl) phenyl]Isoxazol-5-yl]-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.18(d, 6H), 2.63(t, 3H), 3.49(m, 1H), 4.26(m, 2H), 7.25(br s, 2H), 7.63-7.65(m, 2H), 7.85(m, 1H), 7.93(m, 3H), 8.36(m, 2H), 8.87(br s, 2H) and 8.98(s, 1H) ppm; MS (ES) ⁺)498.2

Example 66A: 5- (4- (ethylsulfonyl) phenyl) -3- (5- (3- ((methylamino) methyl) phenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (compound IA-307)

Synthetic route

Compound IA-307

Compound IA-307 was prepared using method IV-AJ step 1 followed by method IV-AAM step 1-3.

Process IV-AAM

Step 1: 5-bromo-3- (5- (4- (bromomethyl) phenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

Dibromo (triphenyl) phosphane (37.29g, 88.35mmol) was added to a suspension of 4- (bromomethyl) benzoic acid (4.318g, 20.08mmol) and 3-amino-6-bromo-pyrazine-2-carboxylic acid hydrazide (4.66g, 20.08mmol) in acetonitrile (143.4 mL). The resulting mixture was stirred at room temperature for 2h, then Hunig's base (15.57g, 20.98mL, 120.5mmol) was added and the reaction stirred overnight. An exotherm was observed during the Hunig base addition; neutralized with an ice bath (temperature maintained at about 20 +/-4). FiltrationThe reaction mixture, washed the resulting solid with cold acetonitrile to give product as a yellow solid (5.45g, 66.7% yield); 1H NMR (400.0MHz, DMSO) d 4.82(s, 2H), 7.72(d, 2H), 7.80(s, 1H), 8.11(d, 2H) and 8.45(s, 1H) ppm; MS (ES)⁺)412.1。

Step 2: 5-bromo-3- (5- (4- ((methylamino) methyl) phenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

Suspension of 5-bromo-3- (5- (4- (bromomethyl) phenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (100mg, 0.2433mmol) and Na₂CO₃(77.36mg, 0.7299mmol) treated with methylamine (182.4. mu.L, 2M, 0.36 mmol). The reaction was heated at 60 ℃ for 10min, then methylamine (426.0 μ L, 2M, 0.86mmol) was added and the reaction was heated at 60 ℃ for a further 10 min. The reaction was cooled, diluted with water (5mL) and extracted into dichloromethane (3 x5 mL). With Na₂SO₄Drying the organic layer, filtering, and vacuum concentrating to obtain 5-bromo-3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine (74.7mg, 85.34% yield) as a yellow solid; MS (ES)⁺)362.3

And step 3: 5- (4- (ethylsulfonyl) phenyl) -3- (5- (4- ((methylamino) methyl) phenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

To a 0.5-2.0mL microwave vial was added 5-bromo-3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine (100mg, 0.24mmol), 4- (ethylsulfonyl) phenylboronic acid (56.72mg, 0.265mmol), dioxane (1mL) and Na₂CO₃Aqueous solution (361.3. mu.L of a 2M solution, 0.72 mmol). Palladium and triphenylphosphine (13.91mg, 0.012mmol) were then added and the vial was sealed. The reaction mixture was heated in a microwave at 150 ℃ for 30 min. Thereafter, the reaction mixture was diluted with DMSO (2mL), filtered, and then purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10. mu.M, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were collected and evaporated to dryness to give the product as a yellow solid (64.35mg, 65% yield); 1H NMR (400.0MHz, DMSO) d 1.14(t, 3H), 2.64(s, 3H), 3.33-3.39(m, 2H), 4.29(s, 2H), 7.77(d, 2H), 8.02(d, 2H), 8.26(d, 2H), 8.41(d, 2H), 8.93(s, 2H) and 9.09(s, 1H) ppm; MS (ES)⁺)451.0

All of the following compounds were prepared using procedures analogous to those described above for compound IA-307.

Compound IA-2895- [4- (2-dimethylaminoethylsulfonyl) phenyl]-3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazine-2-amine MS (ES)⁺)494.0

Compound IA-2964- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N, N-dimethyl-benzenesulfonamide 1HNMR (400.0MHz, DMSO) d 2.64(t, 3H), 2.67(s, 6H), 4.28-4.30(m, 2H), 7.76(d, 2H), 7.88(d, 2H), 8.26(d, 2H), 8.40(d, 2H), 8.92(s, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)466.0

Compound IA-2975- [4- (azetidin-1-ylsulfonyl) phenyl]-3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl ]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 2.01(td, 2H), 2.64(s, 3H), 3.72(t, 4H), 4.29(s, 2H), 7.77(d, 2H), 7.94(d, 2H), 8.26(d, 2H), 8.45(d, 2H), 8.94(s, 2H) and 9.10(s, 1H) ppm; MS (ES)⁺)478.0

Compound IA-3013- [4- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]Phenyl radical]Sulfonylpropan-1-ol 1HNMR (400.0MHz, DMSO) d 1.71(dd, 2H), 2.64(s, 3H), 3.28-3.45(m, 4H), 4.29(s, 2H), 4.68(s, 1H), 7.77(d, 2H), 8.02(d, 2H), 8.27(d, 2H), 8.41(d, 2H), 8.90(s, 2H) and 9.09(s, 1H) ppm; MS (ES)⁺)481.0

Compound IA-3023- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-tetrahydrofuran-3-ylsulfonylphenyl) pyrazine2-amine 1H NMR (400.0MHz, DMSO) d 2.14-2.20(m, 2H), 2.64(s, 3H), 3.66(dd, 1H), 3.77(dd, 1H), 3.86(dd, 1H), 4.05(dd, 1H), 4.23-4.26(m, 1H), 4.29(s, 2H), 7.77(d, 2H), 8.05(d, 2H), 8.26(d, 2H), 8.42(d, 2H), 8.94(s, 2H) and 9.09(s, 1H) ppm; MS (ES)⁺)493.0

Compound IA-3044- [ 5-amino-6- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]-N- (2-hydroxyethyl) benzenesulfonamide 1HNMR (400.0MHz, DMSO) d 2.63(d, 3H), 2.84(q, 2H), 3.39(t, 2H), 4.29(s, 2H), 7.74(q, 1H), 7.78(s, 2H), 7.93(d, 2H), 8.26(d, 2H), 8.34(d, 2H), 8.99(s, 2H) and 9.05(s, 1H) ppm; MS (ES) ⁺)482.0

Compound IA-3083- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- [4- (Oxopropyl-3-ylsulfonyl) phenyl]Pyrazin-2-amine 1HNMR (400.0MHz, DMSO) d 2.64(s, 3H), 4.29(s, 2H), 4.77-4.82(m, 4H), 4.96(s, 1H), 7.77(d, 2H), 8.05(d, 2H), 8.26(d, 2H), 8.41-8.43(m, 2H), 8.89(s, 2H) and 9.09(s, 1H) ppm; MS (ES)⁺)479.0

Compound IA-3103- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-propylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 0.94(t, 3H), 1.60(q, 2H), 2.64(s, 3H), 3.32-3.36(m, 1H), 4.29(s, 2H), 7.77(d, 2H), 8.02(d, 2H), 8.26(d, 2H), 8.39-8.41(m, 2H), 8.95(d, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)465.0

Compound IA-3133- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-sec-butylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 0.94(t, 3H), 1.19(d, 3H), 1.32-1.40(m, 1H), 1.89-1.83(m, 1H), 2.28(d, 3H), 3.26-3.31(m, 1H), 3.76(s, 2H), 7.61(d, 2H), 7.98(d, 2H), 8.12(d, 2H), 8.40(d, 2H) and 9.06(s, 1H) ppm; MS (ES)⁺)479.0

The compound IA-2883- [5- [4- (methylaminomethyl) phenyl ]-1, 3, 4-oxadiazol-2-yl]-5- (4-methyl)Phenylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 2.64(s, 3H), 3.29(s, 3H), 4.29(s, 2H), 7.77(d, 2H), 8.06(d, 2H), 8.26(d, 2H), 8.39-8.41(m, 2H), 8.92(s, 2H), and 9.09(s, 1H) ppm; MS (ES)⁺)437.0

Compound IA-3233- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-tetrahydropyran-4-ylsulfonylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.52-1.63(m, 2H), 11.78(d, 2H), 2.64(t, 3H), 3.30(dd, 2H), 3.57-3.64(m, 1H), 3.92(dd, 2H), 4.28-4.30(m, 2H), 7.77(d, 2H), 7.98(d, 2H), 8.26(d, 2H), 8.41-8.43(m, 2H), 8.91(s, 2H) and 9.01(s, 1H) ppm; MS (ES)⁺)507

Compound IA-3245- [4- [2- (dimethylamino) -1-methyl-ethyl]Sulfonylphenyl]-3- [5- [4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.30(d, 3H), 2.64(s, 3H), 2.81(s, 3H), 2.90(s, 3H), 3.35(s, 1H), 3.56(s, 1H), 4.09(s, 1H), 4.29(s, 2H), 7.77(d, 2H), 7.90-7.97(m, 2H), 8.06(d, 2H), 8.25(d, 2H), 8.47(d, 2H), 9.03(s, 2H), 9.13(s, 1H) and 9.65(s, 1H) ppm; MS (ES) ⁺)508

Compound IA-3284- [4- [ 5-amino-6- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]Phenyl radical]Sulfonyl-2-methyl-pentan-2-ol MS (ES)⁺)541

Compound IA-3323- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- [4- (3-methoxy-1-methyl-propyl) sulfonylphenyl]Pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d 1.24(d, 3H), 1.51-1.57(m, 1H), 2.07-2.14(m, 1H), 2.67(s, 3H), 3.22(s, 3H), 3.40-3.45(m, 3H),), 4.33(s, 2H), 7.62(m, 1H), 7.72(d, 1H), 8.02(d, 2H), 8.31(t, 1H), 8.40(d, 2H), 9.06(s, 2H) and 9.12(s, 1H) ppm; MS (ES)⁺)528

Compound IA-3383- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-sec-butylsulfonylphenyl)) Pyrazine-2-amine MS (ES)⁺)497

The compound IA-3443- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-tetrahydropyran-4-ylsulfonylphenyl) pyrazin-2-amine 1HNMR (400.0MHz, DMSO) d 1.52-1.63(m, 2H), 1.77(d, 2H), 2.64(s, 3H), 3.30(dd, 2H), 3.56-3.64(m, 1H), 3.92(dd, 2H), 4.31(s, 2H), 7.60(dd, 1H), 7.68-7.70(m, 1H), 7.98(d, 2H), 8.28(t, 1H), 8.37-8.39(m, 1H), 8.98(s, 2H) and 9.09(s, 1H) ppm; MS (ES) ⁺)525

Compound IA-3473- [5- [ 2-fluoro-4- (methylaminomethyl) phenyl]-1, 3, 4-oxadiazol-2-yl]-5- (4-tetrahydrofuran-3-ylsulfonylphenyl) pyrazin-2-amine 1HNMR (400.0MHz, DMSO) d 2.13-2.20(m, 2H), 2.64(s, 3H), 3.66(dd, 1H), 3.74-3.80(m, 1H), 3.86(m, 1H), 4.04(m, 1H), 4.22-4.28(m, 1H), 4.31(s, 2H), 7.60(dd, 1H), 7.69(d, 1H), 8.05(d, 2H), 8.29(t, 1H), 8.38(d, 2H), 8.96(s, 2H) and 9.10(s, 1H) ppm; MS (ES)⁺)511

Compound I A-3305- [4- (3-methoxy-1-methyl-propyl) sulfonylphenyl]-3- [5- [4- (methylaminomethyl) phenyl 1, 3, 4-oxadiazol-2-yl]Pyrazine-2-amine MS (ES)⁺)509

Example 67A: 2- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] -5- (methylaminomethyl) phenol (compound IA-291)

Synthetic route

Compound IA-291

Compound IA-291 was prepared using method IV-C, step 1-2, then using method IV-AR, step 1-2, then using method IV-AAN, step 1.

Process IV-AAN

Step 1: 2- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ] -1, 3, 4-oxadiazol-2-yl ] -5- (methylaminomethyl) phenol

To N- [ [4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl ]-1, 3, 4-oxadiazol-2-yl]-3-chloro-phenyl]Methyl radical]To a solution of tert-butyl (N-methyl-carbamate) (130mg, 0.2170mmol) in dioxane (3mL) was added 1, 5-diphenylpenta-1, 4-dien-3-one, palladium (6.239mg, 0.01085mmol), di-tert-butyl- [2- (2, 4, 6-triisopropylphenyl) phenyl ] methyl-carbamate]Phosphine (13.82mg, 0.03255mmol) and potassium hydroxide (434.0 μ L, 1M, 0.4340 mmol). The resulting mixture was heated to 100 ℃ for 2 h. Further, 1, 5-diphenylpenta-1, 4-dien-3-one, palladium (6.239mg, 0.01085mmol) and di-tert-butyl- [2- (2, 4, 6-triisopropylphenyl) phenyl group were added]Phosphine (13.82mg, 0.03255mmol) and potassium hydroxide (434.0 μ L, 1M, 0.4340mmol), and the resulting mixture was heated at 100 ℃ for an additional 2 h. The reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography eluting with 20% EtOAc/petroleum ether. The product fractions were combined and concentrated in vacuo. The mixture was dissolved in DCM (10mL) and TFA (247.4mg, 167.2. mu.L, 2.170mmol) was added. The resulting mixture was stirred at room temperature for 1h, then concentrated in vacuo to an oil. It was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH) ₃CN) within 16 minutes, 25mL/min]. The product fractions were collected and lyophilized to give the product as a yellow solid (24.0mg, 18% yield); 1H NMR (400.0MHz, DMSO) d 1.31(m, 6H), 2.80(s, 3H), 3.43(m, 1H), 4.27(s, 2H), 7.23(m, 1H), 7.30(m, 1H), 8.04(m, 2H), 8.19(m, 1H), 8.41(m, 2H) and 8.95(s, 1H) ppm; MS (ES)⁺)481.2

All of the following compounds were prepared using a similar procedure as described above for compound I-291.

Compound I-3205- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]-2- (methylaminomethyl) phenol 1H NMR (400.0MHz, DMSO) d 1.3(d, 6H), 2.7(s, 3H), 3.4-3.5(m, 1H), 4.45(s, 2H), 7.7(d, 1H), 7.8-7.83(m, 2H), 8.05(d, 2H), 8.4(d, 2H) and 8.95(s, 1H) ppm; MS (ES)⁺)481.2

Example 67A: 2- [ 5-amino-6- (5-phenyl-1, 3, 4-thiadiazol-2-yl) pyrazin-2-yl ] -5- (1, 4-diazepan-1-carbonyl) benzonitrile (Compound IVA-2)

Synthetic route

Compound IAV-2

Compound IVA-2 was prepared using method IV-D, step 1, followed by method IV-AAO, step 1.

Process IV-AAO

Step 1: 2- [ 5-amino-6- (5-phenyl-1, 3, 4-thiadiazol-2-yl) pyrazin-2-yl ] -5- (1, 4-diazepan-1-carbonyl) benzonitrile

A mixture of 4-bromo-3-cyano-benzoic acid methyl ester (100mg, 0.4166mmol), potassium acetate (122.7mg, 1.250mmol), 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolan (158.7mg, 0.6249mmol) and 1-cyclopentyl-1, 4-dienyl-diphenyl-phosphine, dichloromethane, dichloropalladium, iron (34.02mg, 0.04166mmol) was heated in dioxane (10mL) at 80 ℃ for 2 h. Thereafter, the reaction mixture was cooled, palladium, triphenylphosphine (48.14mg, 0.04166mmol), sodium carbonate (625.0 μ L, 2M, 1.250mmol) and 5-bromo-3- (5-phenyl-1, 3, 4-thiadiazol-2-yl) pyrazin-2-amine (139.2mg, 0.4166mmol) were added and heated at 140 ℃ under microwave conditions for 1 h. After cooling to room temperature, the resulting carboxylic acid was filtered off as a brown solid. Will be provided withThe solid was dissolved in DMF (3mL) and 1, 4-diazepane (208.3mg, 2.083mmol) and TBTU (267.5mg, 0.8332mmol) was added. The resulting mixture was stirred at room temperature for 2h, then diluted with ethyl acetate (5mL), the organic extracts were washed with water (1X5mL) and brine (1X5mL), and MgSO₄Dried and concentrated in vacuo to give a solid. The solid was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M, Column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were collected and lyophilized to give the product as a yellow solid (60mg, 25% yield); 1H NMR (400.0MHz, DMSO) d 1.9-2.1(m, 2H), 3.3-3.4(m, 4H), 3.5-3.55(m, 2H), 3.65-3.7(m, 1H), 3.7-3.75(m, 1H), 3.8-3.9(m, 2H), 7.5-7.6(m, 3H), 7.8(d, 1H), 8.1-8.22(m, 3H), 8.25(brs, 1H), 8.75 (brs, 2H) and 8.8(s, 1H) ppm; MS (ES)⁺)483.2

All of the following compounds were prepared using a similar procedure as described above for compound IVA-2.

Compound IVA-14- [ 5-amino-6- (5-phenyl-1, 3, 4-thiadiazol-2-yl) pyrazin-2-yl]-3-cyano-N, N-dimethyl-benzamide 1H NMR (400.0MHz, DMSO) d3.0(d, 6H), 7.6-7.65(m, 3H), 7.85(d, 1H), 8.1-8.2(m, 4H), 8.25(br s, 1H) and 8.8(s, 1H) ppm; MS (ES)⁺)428.1

Example 68A: 4- [ 5-amino-6- [5- (2-cyanoanilino) -1, 3, 4-thiadiazol-2-yl ] pyrazin-2-yl ] -N, N-dimethyl-benzamide (compound IVA-3)

Synthetic route

Compound IVA-3

Compound IVA-3 was prepared using method IV-C, step 1-2, followed by method IV-AAP, step 1.

Process IV-AAP

4- (5-amino-6- (hydrazinocarbonyl) pyrazin-2-yl) -N, N-dimethylbenzamide (75mg, 0.2373mmol), 2-isothiocyanatobenzonitrile (38.01mg, 0.2373mmol) in CH₂Cl₂The mixture in (1.425mL) was stirred at room temperature for 2 h. Diethyl ether was added and the reaction mixture was filtered to give a yellow solid. It was dissolved in anhydrous acetonitrile (1.5mL) and then cooled with an ice bath. DIPEA (92.01mg, 124.0. mu.L, 0.7119mmol) was added followed by stepwise addition of dibromo (triphenyl) phosphane (130.2mg, 0.3085 mmol). The resulting mixture was stirred at room temperature overnight and then heated at reflux for 1 h. The reaction mixture was cooled to room temperature and then filtered. The solid was washed with acetonitrile (5mL) and dried in vacuo to give the product as a bright yellow solid (68.0mg, 62% yield); 1H NMR (400.0MHz, DMSO) d 3.01(d, 6H), 5.76(s, 2H), 7.55-7.60(m, 3H), 7.73(d, 1H), 7.83-7.87(m, 2H), 8.18(d, 2H), 8.43-8.45(m, 1H) and 8.91(s, 1H) ppm; MS (ES)⁺)443.17

Example 69A: 3- [3- [ 2-fluoro-4- (methylaminomethyl) phenyl ] isoxazol-5-yl ] -5- (4-tetrahydrofuran-3-ylsulfonylphenyl) pyrazin-2-amine (compound IIA-16)

Synthetic route

Compound IIA-16

Compounds IIA-16 were prepared using method IV-F step 1-2, then method IV-AAD step 1-2, then method IV-AAQ step 1.

Process IV-AAQ

Step 1: 3- [3- [ 2-fluoro-4- (methylaminomethyl) phenyl ] isoxazol-5-yl ] -5- (4-tetrahydrofuran-3-ylsulfonylphenyl) pyrazin-2-amine

TFA (281.6mg, 190.3. mu.L, 2.470mmol) was added to N- [ [4- [5- [3- [ bis (tert-butoxycarbonyl) amino ] at room temperature]-6- (4-tetrahydrofuran-3-ylsulfonylphenyl) pyrazin-2-yl]Isoxazol-3-yl]-3-fluoro-phenyl]Methyl radical]-N-methyl-carbamic acid tert-butyl ester (100mg, 0.1235mmol) in dichloromethane (2.069mL) and the resulting solution was stirred for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were collected and lyophilized to give the product as a yellow solid (34.0mg, 44% yield); 1H NMR (400.0MHz, DMSO) d 2.13-2.19(m, 2H), 2.63(m, 3H), 3.66(m, 1H), 3.76(m, 1H), 3.85(m, 1H), 4.04(m, 1H), 4.21-4.28(m, 3H), 7.27(m, 2H), 7.52(m, 1H), 7.60-7.65(m, 2H), 8.00(m, 2H), 8.12(t, 1H), 8.36(m, 2H) and 8.94(m, 3H) ppm; MS (ES)⁺)510.2

Example 70A: 3- [5- [4- [ (1S) -1-amino-2, 2, 2-trifluoro-ethyl ] phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound IA-325)

Synthetic route

Compound IA-325

Compounds I A-325 were prepared using method IV-B, steps 1-4, followed by method IV-AAR, step 1.

Process IV-AAR

Step 1: 3- [5- [4- [ (1S) -1-amino-2, 2, 2-trifluoro-ethyl ] phenyl ] -1, 3, 4-oxadiazol-2-yl ] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine

HCl (35.27. mu.L, 3M, 0.1058mmol) was added to N- [ (1S) -1- [4- [5- [ 3-amino-6- (4-isopropylsulfonylphenyl) pyrazin-2-yl]-1, 3, 4-oxadiazol-2-yl]Phenyl radical]-2, 2, 2-trifluoro-ethyl]-2-methyl-propane-2-sulfonamide (253.3mg, 0.05288mmol) in MeOH (1mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure, the residue triturated with acetonitrile and filtered. The solid was dissolved in an acetonitrile/water/MeOH mixture and passed through a bicarbonate column. The eluate was concentrated in vacuo and then triturated with acetonitrile to give the product as a yellow solid (26mg, 99% yield); 1H NMR (400.0MHz, DMSO) d 1.20(d, 6H), 2.68(d, 2H), 3.41-3.51(m, 1H), 4.65-4.75(m, 1H), 7.81(d, 2H), 7.98(d, 2H), 8.20(d, 2H), 8.41(d, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)519.1

Example 71A: 5- [4- [2- (dimethylamino) -1-methyl-ethyl ] sulfonylphenyl ] -3- [5- (2-fluorophenyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine (compound IA-337)

Synthetic route

Compound IA-337

Compound IA-337 was prepared using method IV-AAS, steps 1-2.

Process IV-AAS

Step 1: 5-bromo-3- (5- (2-fluorophenyl) -1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine

To a suspension of 2-fluorobenzoylhydrazine (2g, 12.98mmol), 3-amino-6-bromo-pyrazine-2-carboxylic acid (2.830g, 12.98mmol) and TBTU (5.002g, 15.58mmol) in DMF (20.00mL) was added DIPEA (3.691g, 4.974mL, 28.56 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20mL), extracted with EtOAc (3X20mL), and the combined organic extracts were washed with water (3X20mL) and brine (1X 20mL), and MgSO₄Drying and vacuum concentrating. The residue was then triturated with acetonitrile, filtered, and dried to give 3-amino-6-bromo-N' - (2-fluorophenylcarbonyl) pyrazine-2-carboxylic acid hydrazide as an orange solid. This was dissolved in MeCN (20.00mL), bromo (triphenyl) phosphonium (5.331g, 15.58mmol) was added, followed by DIPEA (3.691g, 4.974mL, 28.56 mmol). The reaction mixture was stirred for 30min and then filtered. The solid was washed with acetonitrile to give the product as a yellow solid (1.46g, 67%); 1H NMR (400MHz, DMSO) d 7.48-7.54(m, 2H), 7.75(m, 3H), 8.12(m, 1H) and 8.45(m, 1H) ppm; MS (ES) ⁺)338.03

Step 2: 5- [4- [2- (dimethylamino) -1-methyl-ethyl ] sulfonylphenyl ] -3- [5- (2-fluorophenyl) -1, 3, 4-oxadiazol-2-yl ] pyrazin-2-amine

2- (4-bromophenyl) sulfonyl-N, N-dimethyl-propan-1-amine (100mg, 0.3233mmol) was dissolved in dioxane (1.774mL) and pinacol diboron (123.6mg, 0.4866mmol) and potassium acetate (95.50mg, 0.9731mmol) were added. The mixture was degassed, purged with nitrogen for 5 minutes, and then Pd (dppf) Cl was added₂DCM (26.40mg, 0.03233mmol) and the mixture was heated to 90 ℃ for 2 h. The reaction mixture was cooled to room temperature to allow N₂Foaming for 10 min. Then 5-bromo-3- (5-phenyl-1, 3, 4-oxadiazol-2-yl) pyrazin-2-amine (102.9mg, 0.3233mmol) and Na were added₂CO₃Aqueous solution (485.0. mu.L, 2M, 0.9699 mmol). Then make N₂Foaming for 10min, then adding Pd (PPh)₃)₄(37.47mg, 0.03243mmol) and the reaction mixture is heated to 30 min at 150 ℃ under microwave conditions. The reaction mixture was passed through a SCX-2 column, eluted with MeCN/MeOH, with 200mL, then 2M NH containing MeCN₃Is washed with a solution of MeOH in water and,to elute the compound. Evaporation of the solvent gave a brown solid which was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH) ₃CN) within 16 minutes, 25mL/min]. The product fractions were collected and lyophilized to give the product as a yellow solid (67.1mg, 33% yield); 1H NMR (400.0MHz, DMSO) d 1.29(d, 3H), 2.80(s, 3H), 2.90(s, 3H), 3.35(d, 1H), 3.48(d, 1H), 4.09(s, 1H), 7.50-7.60(m, 2H), 7.76-7.81(m, 1H), 8.06(d, 2H), 8.20(m, 1H), 8.43(d, 2H), 9.12(s, 1H) and 9.41(s, 1H) ppm; MS (ES)⁺)483

All of the following compounds were prepared using procedures analogous to those described above for compound IA-337.

The compound IA-3273- [5- (2-fluorophenyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-tetrahydropyran-4-ylsulfonylphenyl) pyrazin-2-amine MS (ES)⁺)482

The compound IA-3393- [4- [ 5-amino-6- [5- (2-fluorophenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-yl radicals]Phenyl radical]Sulfonylbutan-1-ol 1H NMR (400.0MHz, DMSO) d1.20(d, 3H), 1.37-1.46(m, 1H), 1.99-2.02(m, 1H), 3.38-3.43(m, 2H), 3.52(s, 1H), 4.66(t, 1H), 7.50-7.59(m, 2H), 7.77(d, 1H), 7.97(d, 2H), 8.20(s, 1H), 8.37(d, 2H) and 9.08(s, 1H) ppm; MS (ES)⁺)470

Compound IA-3435- [4- [3- (dimethylamino) -1-methyl-propyl]Sulfonylphenyl]-3- [5- (2-fluorophenyl) -1, 3, 4-oxadiazol-2-yl]Pyrazin-2-amine 1HNMR (400.0MHz, DMSO) d1.20(d, 3H), 1.76-1.82(m, 1H), 2.14-2.20(m, 1H), 2.79(s, 6H), 3.21(s, 2H), 3.47-3.55(m, 1H), 7.50-7.59(m, 2H), 7.75-7.81(m, 1H), 8.01(d, 2H), 8.19(m, 1H), 8.40(d, 2H), 9.10(s, 1H) and 9.58(s, 1H) ppm; MS (ES) ⁺)497

The compound IA-3493- [5- (2-fluorophenyl) -1, 3, 4-oxadiazol-2-yl]-5- (4-tetrahydrofuran-3-ylsulfonic acidAcylphenyl) pyrazin-2-amine 1H NMR (400.0MHz, DMSO) d2.13-2.19(m, 2H), 3.65(m, 1H), 3.74-3.80(m, 1H), 3.86(dd, 1H), 4.04(dd, 1H), 4.22-4.28(m, 1H), 7.50-7.60(m, 2H), 7.75-7.80(m, 1H), 8.04(d, 2H), 8.20(m, 1H 0, 8.38(d, 2H), and 9.09(s, 1H) ppm; MS (ES)⁺)468

Example 72A: 3- (3- (4- ((dimethylamino) methyl) -2-fluorophenyl) isoxazol-5-yl) -5- (3-fluoro-4- (isopropylsulfonyl) phenyl) pyrazin-2-amine (compound IIA-17)

Synthetic route

Compound IIA-17

Compounds IIA-17 were prepared using method IV-F steps 1-4, followed by method IV-AAT step 1.

Reacting N- [ [4- [5- [3- [ bis (tert-butyloxycarbonyl) amino group]-6-bromo-pyrazin-2-yl]Isoxazol-3-yl]-3-fluoro-phenyl]Methyl radical]-N-methyl-carbamic acid tert-butyl ester (150mg, 0.2211mmol), 2- (3-fluoro-4-isopropylsulfonyl-phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (72.57mg, 0.2211mmol) and Na₂CO₃(46.87mg, 0.4422mmol) was suspended in MeCN (2.486 mL)/water (2.486 mL). Degassing the mixture (x 5N)₂Vacuum cycle), addition of Pd (PPh)₃)₄(25.55mg, 0.02211 mmol). The mixture was degassed again and the reaction mixture was heated at 90 ℃ for 20min under microwave conditions. The reaction mixture was diluted with water (5mL) and ethyl acetate (5mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 10mL) and MgSO ₄The combined organic extracts were dried and concentrated in vacuo. The residue was dissolved in dichloromethane (3mL) and TFA (504.2mg, 340.7. mu.L, 4.422mmol) was added. The resulting solution was stirred at room temperature for 4h, then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [ Waters Sunfire C18, 10 μ M,column, gradient 10% -95% B (solvent A: 0.05% aqueous TFA; solvent B: CH)₃CN) within 16 minutes, 25mL/min]. The product fractions were collected and lyophilized to give the product as a yellow solid (47.5mg, 45% yield); MS (ES)⁺)500.1

Compounds P73-P144, P145, P147-P148 and P150 can be prepared using methods analogous to those described in method AAT.

The compounds of table a were synthesized using the methods described herein and methods well known in the art. More specifically, these compounds are prepared using one or more of the following methods: oxadiazolyl compounds (compounds of formula I A) can be prepared according to the methods described in schemes I-B2 and I-B3; isoxazolyl compounds (compounds of formula IIA) can be prepared according to the methods described in schemes I-E1 and I-E2. The triazolyl compounds (formula IIIA) were prepared according to the procedures described in schemes I-F1 and I-F2.

TABLE A

Example 73A: 3-amino-N- (1H-benzo [ d ] imidazol-2-yl) -6- (4- (dimethylcarbamoyl) phenyl) pyrazine-2-carboxamide (Compound V-1)

Synthetic route

Compound I-1

Preparation of Compound V-1 Using Process V-A, Steps 1-2

Method V-A:

step 1: 3-amino-6- (4- (dimethylcarbamoyl) phenyl) pyrazine-2-carboxylic acid

3-amino-6-bromo-pyrazine-2-carboxylic acid methyl ester (6.01g, 25.9mmol, 1.0Eq.), 4- (dimethylcarbamoyl) phenylboronic acid (5.00g, 25.9mmol, 1.0Eq.), Na₂CO₃(5.49g, 51.8mmol, 2.0Eq.) and Pd (PPh)₃)₄(2.99g, 2.59mmol, 0.1Eq.) was heated in acetonitrile (30mL) and water (30mL) at 90 ℃ for 16 h. Cooling to the ringAfter ambient temperature, the precipitate was removed by filtration. The aqueous filtrate was acidified to pH 4 by addition of 1M HCl, then extracted with dichloromethane (3 × 20mL), over MgSO₄Drying and concentration in vacuo afforded the sub-title product as a yellow solid (2.42g, 65% yield). 1HNMR (400.0MHz, DMSO)2.95(3H, br s), 3.00(3H, br s), 7.49-7.51(2H, m), 7.58(2H, br s), 8.1592H, d), 8.95(1H, s), 13.25(1H, br s) ppm; MS (ES)⁺)287.13。

Step 2: 3-amino-N- (1H-benzo [ d ] imidazol-2-yl) -6- (4- (dimethylcarbamoyl) phenyl) pyrazine-2-carboxamide

Amino-6- (4- (dimethylcarbamoyl) phenyl) pyrazine-2-carboxylic acid (112.5mg, 0.3930mmol, 1.0Eq.) in DMF (1.1mL) was treated with 1H-benzoimidazol-2-amine (62.8mg, 0.4716mmol, 1.2Eq.) and triethylamine (39.8mg, 54.8 μ L, 0.3930mmol, 1.0Eq.) followed by TBTU (176.7mg, 0.5502mmol, 1.4 Eq.). The reaction mixture was stirred at ambient temperature overnight and then added dropwise to stirred water (15 ml). It was stirred at ambient temperature for 1 hour, separated by filtration to give a precipitate, and washed with water. The residue was recrystallized from hot acetonitrile to give the title compound as a yellow solid (63.1mg, 40% yield). 1H NMR (400.0MHz, DMSO)2.97(3H, br s), 3.02(3H, br s), 7.15-7.18(2H, m), 7.51-7.55(4H, m), 7.83(2H, br s), 8.34(2H, d), 9.04(1H, s), 11.50(1H, br s), 12.35(1H, br) ppm; MS (ES) ⁺)402.08。

Compounds V-1 to V-30 were also prepared using a method analogous to that for compound V-1.

The compounds of table B were synthesized using the methods described herein and those well known in the art. More specifically, the compounds are prepared using one or more of the following methods: benzothiazolyl compounds may be prepared according to the procedures described in schemes I-H1 and I-H2; benzoxazolyl compounds can be prepared according to the procedures described in schemes I-G1. Benzimidazolyl compounds may be prepared according to the methods described in schemes I-I1 and I-I2. Heteroaromatic amides may be prepared according to the methods described in schemes I-A1 and I-A2.

TABLE B

Example 75A: cell ATR inhibition assay:

compounds were screened for their ability to inhibit intracellular ATR using immunofluorescence microscopy to detect phosphorylation of ATR substrate histone H2AX in hydroxyurea-treated cells. HT29 cells were plated at 14,000 cells/well in McCoy's 5A medium (Sigma M8403) supplemented with 10% fetal bovine serum (JRH Biosciences 12003), 1: 100 diluted penicillin/streptomycin solution (Sigma P7539), and 2mM L-glutamine (Sigma G7513) in 96-well black imaging plates (BD353219) and allowed to stand at 37 ℃ in 5% CO ₂Middle adhesion overnight. The compounds were then added to the cell culture medium starting at a final concentration of 25 μ M in 3-fold serial dilution and the cells were incubated at 37 ℃ in 5% CO₂And (4) carrying out incubation. After 15min hydroxyurea (Sigma H8627) was added to a final concentration of 2 mM.

After treatment of 45 min with hydroxyurea, cells were washed with PBS, fixed in 4% PBS-diluted formaldehyde (Polysciences Inc 18814) for 10min, washed with 0.2% Tween-20 in PBS (wash buffer) and all permeabilized in 0.5% Triton X-100 in PBS for 10min at room temperature. The cells were then washed once with wash buffer and blocked in 10% goat serum (SigmaG9023) diluted with wash buffer (blocking buffer) for 30min at room temperature. To detect the level of H2AX phosphorylation, cells were then incubated for 1H at room temperature in a primary antibody (mouse monoclonal anti-phosphohistone H2AX Ser 139 antibody; Upstate 05-636) diluted 1: 250 in blocking buffer. The cells were then washed 5 times with wash buffer and then incubated for 1H at room temperature in the dark in a mixture of secondary antibody (goat anti-mouse Alexa Fluor 488 conjugated antibody; Invitrogen A11029) and Hoechs t dye (Invitrogen H3570) diluted 1: 500 and 1: 5000 with wash buffer, respectively. Cells were then washed 5 times with wash buffer and finally 100ul PBS was added to each well before imaging.

Cells were imaged for Alexa Fluor 488 and Hoechst intensity using BD Pathway 855 Bioimager and Attovision software (BD Biosciences, version1.6/855) to quantify phosphorylated H2AX Ser139 and DNA staining, respectively. The percentage of phosphorylated H2 AX-positive nuclei in the montage of 9 images at 20x magnification was then calculated for each well using BD Image Data Explorer software (BD Biosciences version 2.2.15). Phosphorylated H2 AX-positive nuclei were defined as the Hoechst-positive region of interest, which contained Alexa Fluor 488 intensity at 1.75-fold the average Alexa Fluor 488 intensity in cells not treated with hydroxyurea. The percentage of H2AX positive nuclei was finally plotted against the concentration of each compound and the IC50s of intracellular ATR inhibition was determined using Prism Software (GraphPad Prism version 3.0cx by Macintosh, GraphPad Software, san diego California, USA).

The compounds described herein may also be tested according to other methods known in The art (see Sarkaria et al, "Inhibition of ATM and ATR Kinase activity by The Radiosensing Agent, Cancer: Cancer Research 59: 4375-5382 (1999); Hickson et al," Identification and specificity of The Ataxia-Telangiectasia Mutated kit ATM "Cancer Research 64: 9152-9159 (2004); Kim et al," Inhibition of specificity and Identification of purification of The ATM Kinase domain genes "JournaL of Biological Chemistry 3753 and amplification of Biological genes 3753 and 3. see" Cancer Research 3-34. The methods of culture of microorganisms of The present invention: 97. The methods of culture of mTOR et al., The methods of culture of Biological 3. The present invention is also described in FIGS. 7, FIGS. 11, 3, a, and a, a.

Example 76A: ATR inhibition assay:

the ability of a test compound to inhibit ATR kinase is screened using a radioactive phosphate incorporation assay. In 50mM Tris/HCl (pH 7.5), 10mM MgCl₂And 1mM DTT mixture. The final substrate concentration was 10. mu.M [ gamma-33P ]]ATP (3mCi 33P ATP/mmol ATP, Perkin Elmer) and 800. mu.M of the target peptide (ASELPASQPQPFSAKKK).

The assay was performed at 25 ℃ in the presence of 5nM full length ATR. Assay stock buffer solutions were prepared containing all of the above-mentioned reagents, except for ATP and the test compound of interest. 13.5 μ L of stock solution was placed into 96-well culture plates, and then 2 μ L of DMSO stock solution containing test compounds in serial dilutions (typically starting from 15 μ M final concentration using 3-fold serial dilutions), was added in duplicate (final DMSO concentration of 7%). The plates were preincubated at 25 ℃ for 10 min and the reaction was initiated by addition of 15. mu.L [ gamma. -33P ] ATP (final concentration 10. mu.M).

The reaction was stopped after 24 hours by adding 30. mu.L of 0.1M phosphoric acid containing 2mM ATP. Multi-screen phosphocellulose filter 96-well plates (Millipore, Cat. No. MAPNN 0B50) were pretreated with 100. mu.L of 0.2M phosphoric acid, followed by addition of 45. mu.L of the stop assay mixture. The plate was washed with 5X 200. mu.L of 0.2M phosphoric acid. After drying, 100 μ L of Optiphase 'Supermix' Liquid Scintillation cocktail (Perkin Elmer) was added to the well, followed by Scintillation counting (1450Microbeta Liquid Scintillation Counter, Wallac).

After removing the average background value for all data points, ki (app) data was calculated from nonlinear regression analysis using the Prism Software package (GraphPadPrism version 3.0cx by Macintosh, GraphPad Software, San Diego California, USA).

The following is a graph showing the Ki values for ATR inhibition for the compounds of the present specification. Compounds with Ki values ≦ 10nM are labeled with "+++". Compounds with Ki values > 10nM, but ≦ 100nM are labeled with "+ +". Compounds with Ki values > 100nM, but ≦ 5uM, were labeled with "+".

Example 77A: cisplatin sensitization test

Compounds were screened for the ability to sensitize HCT116 colorectal cancer cells to cisplatin using a 96h cell survival (MTS) assay. HCT116 cells with ATM signaling defects in cisplatin (see Kim et al; Oncogene 21: 3864 (2002); see also Takemura et al; JBC 281: 30814(2006)) were plated at 470 cells/well in 150. mu.l McCoy's 5A medium (Sigma M8403) supplemented with 10% fetal bovine serum (JRH Biosciences 12003), 1: 100 diluted penicillin/streptomycin solution (SigmaP7539), and 2mM L-glutamine (Sigma G7513) in 96-well polystyrene culture plates (Costar 3596) and allowed to incubate at 37 ℃ at 5% CO 7513 ₂Middle adhesion overnight. The compound and cisplatin were then added simultaneously to the cell culture medium starting at a final concentration of 10 μ M in 2-fold serial dilution as the complete matrix concentration in a final cell volume of 200 μ l, and the cells were then incubated at 37 ℃ in 5% CO₂And (4) carrying out incubation. After 96h, 40. mu.l of MTS reagent (Promega G358a) was added to each well and cells were incubated at 37 ℃ in 5% CO₂Incubated for 1 h. Finally, absorbance was measured at 490nm using a SpectraMax Plus 384 reader (Molecular Devices) and the concentration of compound required to reduce the IC50 of cisplatin alone by at least 3-fold (to 1 decimal place) was reported.

Compounds with I C50 or Ki values ≦ 100nM are labeled with "+++". Compounds with IC50 or Ki values > 100nM, but ≦ 1uM, were labeled with "+ +". Compounds with IC50 or Ki values > 1uM, but ≦ 20uM, were labeled with "+".

Watch C

While we have described a number of embodiments of this invention, it is apparent that our basic examples can be modified to provide other embodiments using the compounds, methods and processes of this invention. It is, therefore, to be understood that the scope of the invention is defined by the appended claims rather than by the specific embodiments which are presented as examples herein.

Claims

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating colorectal cancer in a patient.

4. The use of claim 3, further comprising an additional therapeutic agent selected from cisplatin.

5. Use of a compound of claim 1 in the manufacture of a medicament for promoting cell death in colorectal cancer cells.

6. The use of claim 5, wherein said cell is a cancer cell having a defect in the ATM signaling cascade.

7. The use of claim 6, wherein the defect is altered expression or activity of one or more of ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, or H2 AX.

8. The use of claim 5, wherein the cell is a cancer cell expressing a DNA damaging oncogene.

9. The use of claim 8, wherein the cancer cell has altered expression or activity of one or more of K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, Cdc4, CDK2, cyclin E, cyclin a, and Rb.

10. Use of a compound of claim 1 for the manufacture of a medicament as a single active agent for the treatment of colorectal cancer.

11. Use of a compound of claim 1 for the manufacture of a medicament for treating a patient having colorectal cancer with a deficiency in DNA-damage response.

12. The use of claim 11, wherein the defect is a mutation or deletion of ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 or H2 AX.