UA99175C2 - Compounds and compositions as tlr activity modulators - Google Patents

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with Toll-Like Receptors, including TLR7 and TLR8. In one aspect, the compounds are useful as adjuvants for enhancing the effectiveness of a vaccine (formula I) wherein: Xis N; Xis N Or CR; Xs is –CR=CR.

Description

Swheteroalkyl, C1-Swhaloalkyl, C3-Swalkene, C0-Swalkyne, C1-Swallowoxy, C1-Swhaloalkyl, aryl, heteroaryl, C3-Swcycloalkyl, and C3-Swheterocycloalkyl, wherein each of the groups such as: C:i- Svalkil,

Ci-Swheteroalkyl, Ci-Swhaloalkyl, Co-Swalkene, Co-Swalkyne, C--Swalkoxy group, Ci-Swhaloalkoxy group, aryl, heteroaryl, C3-Swcycloalkyl and C3-Swheterocycloalkyl radical K" and KK? is optionally substituted by with the help of 1-3 substituents independently chosen from such as: halogen, -SM, -MO", -B", -

ОВ, -С(0)88, -ОС(О)Н8, -С(О)ОВ8, -М(ВУ)», -РИОХОВВ)», -«ОР(ИОХОВУ)», -Р(ИОХОВ' 9) », -OR(IOHOV'9)», -

C(O)M(AU)", -5(0)288, -5(0)2M(VU)2, and -MAU5(O)2A8; or KZ and P", or KK" and I, when on adjacent ring atoms, may be optionally bonded together to form a 5-6b-membered ring, where the 5-6-membered ring is optional substituted with KK"; each I. is independently chosen from such as: connection, -""O(СНг)т)-, Si-Svalkyl, Co-Svalkenylene and So-

Svalkynylene, where Si-Svalkyl, Co-Svalkynylene and Co-Svalkynylene of the Y radical are each optionally substituted with 1-4 substituents independently selected from such as: halogen, -H8, -OHU, -

М(ВЗ)2, -Р(ОХОНВЗ)», - СОР(ОХОВНЗ)», -Р(ИОХОВ' У)», and -"OR(ОХОВ' У)";

B' is selected from such as: H, C:-Salkyl, aryl, heteroaryl, C3-C8cycloalkyl, C1-C8heteroalkyl, C1-

C-haloalkyl, Co-Swalkene, C-Swalkene, C-C-Swalkoxy group, C-Swhalo-Alkoxy group, and cC3-

S-heterocycloalkyl, where each of the groups such as: C1-Salkyl, aryl, heteroaryl, C3-C1cycloalkyl, C1-

S-Heteroalkyl, C-Ci-Shaloalkyl, Co-Swalkene, Co-Swalkyne, C--Swalkoxy Group, C-Ci-SwhaloAlkoxy Group, and

C3-Swheterocycloalkyl radical K" is optionally substituted with 1-3 B"3 groups, and each K'3 is independently selected from such as: halogen, -CM, -I Be, -HOBe, -ОЙ КУ, -ГА8о, -GOVO, -ОГА о, -И 88, - ОН, -

ОЙ K8, -I588, -158Т, -О(О0)88, -0О1 С(О)Н8В - СО) - С(О)В8, - ОС) - and С(О)МАА", -

IGS(O)MA?A8, -1 (VU), -І MAYA, - MAT - С(О)М(АУ)», -и5(0)288, -и5(0)Н8, -С(О) MAWSON, -

I MAZS(O)VYA, - MAS(OYUVU, -I 5(0)2M(AU)", -OI 5(O)2M(VU)", -IMAUB(O)2AYA, -IS(O)MAI UIA )", -

GR(IFOHOVNVZ)", - ОР(ОХОНВВ)", - Р(ИОХХОВ'О)» and -ОI РИФОХОВ" У); each KZ is independently chosen from the following: Н, -СН(В"9)», Si- Svalkil, So-Svalken, Sgo-Svalkin, Si-

C:-Swhaloalkyl, C:i-Swallowoxy group, C.:-Swheteroalkyl, C3-Swcycloalkyl, C2-Swheterocycloalkyl, C1-

Sw-hydroxyalkyl and C1-Swhaloalkyl group, where each of the groups such as: C1-Swalkyl, Co-Swalkene, C2-

Svalkin, C-Swheteroalkyl, C-Swhaloalkyl, C-Swallowoxy group, C3-Swcycloalkyl, -: C2-

Svheterocycloalkyl, Ci-Swihydroxyalkyl and Ci-Swihaloalkyl group of the KU radical is not necessarily substituted by 1-3 substituents independently selected from such as: -СМ, В", -О8", -58, - сС()вВ" . , -OVO, -

С(О)МА" В, -С(О)МА"ЧОН, -550)28", -5(0)8А", -5(О)2МА"А, -MALO(О)2А", -ROHOV 2", and -

ОР(ОХОВ")»; each K? is independently selected from such as: Н, -С(0)А8, -С(О)ОН8, -С(О)В8О, -Б(О0)ОВо, -5(0 )289, -

C-Cv alkyl, C1i-Cv heteroalkyl and C3-Cv cycloalkyl, or each P? independently represents C.:-Alalkyl, which together with M, to which they are attached, forms C3-Swheterocycloalkyl, where C3-

The α-heterocycloalkyl ring optionally contains an additional heteroatom selected from M, O and 5, and wherein each of the groups such as: C:1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or

Svheterocycloalkyl radical K? is optionally substituted with 1-3 substituents independently selected from such as: -СМ, В", -ОВ", -58", -Ф(О)8", -ОС(О)В", - S(O)OV", - MA "V", -

С(О)МА" В, -С(О)МА"ЧОН, -550)28", -5(0)8А", -5(О)2МА"А, -MALO(О)2А", -ROHOV 2", and -

OR(OHOV")"; each CO? is independently selected from: aryl, C3-Swcycloalkyl, C3-Swheterocycloalkyl or heteroaryl, where groups such as: aryl, C3-Swcycloalkyl, C3-Swheterocycloalkyl or heteroaryl are optional substituted with 1-3 substituents selected from such as: halogen, -H8, -ОНВ, -

M(VU)", -MA?С(О)Н8, -МА?СО»Не, -СО2Н8, -С(О)В8 and -С(О)М(AU)";

A" and B"? independently selected from such as: H, C1-Swalkyl, C1-Swheteroalkyl, C1-Swhaloalkyl, aryl, heteroaryl, C3-Swcycloalkyl, and C3-Swheterocycloalkyl, where each of the groups such as: C1-Swalkyl, C1-

S-heteroalkyl, C-S-haloalkyl, aryl, heteroaryl, C-S-C cycloalkyl, and C-S-S heterocycloalkyl, radicals K"' and K!? are optionally substituted with 1-3 substituents independently selected from such as: halogen, -CM 88

C(O)M(BAU)", C3-Swheterocycloalkyl, -5(O0)2A8, -5(0)2M(НЗ)", -MAZ5(O)2NU, C-Swhaloalkyl and cS--

A haloalkoxy group, and where each of the aryl and heteroaryl groups of the radical KK" and B: is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, 8, -ОБ8, -С(О )НА8, ОС(О)Б8, -С(ООН8, -М(АУ)», -С(О)М(AZ)», C3-Swheterocycloalkyl, -5(0)2Н8, - 5(0)2 M (VU)", -MA?5(O)2H88, C1-Cvhaloalkyl and C1-Cvhaloalkyloxy group; or KE" and K" each independently represents C-Cvalkyl and taken together with the M atom to which they are attached form an optionally substituted C3-Swheterocycloalkyl ring optionally containing an additional heteroatom selected from M, O and 5;

Ring A is aryl or heteroaryl, where aryl and heteroaryl groups. Rings A are optionally substituted with 1-3 B" groups, where each K" is independently selected from such as: - ve, -B7, -ОВ", -ОВ8, -Во, -О8О, -588, -МО", -СМ, -М(ВУ)2, -МАЗС(О)Н8, -МАУС(5)А8, -МАС(О)М(AZ)", -

MA?S(5)M(AYA)», -MAZSO2A8, -MA"MA?S(O)NYA, /-MAMAS(O)M(AU)», -MA"MAZSO»VU, -SB(0) С(О)Н88, -

С(О)СНоС(О)ВВ, -СО2Н88, -«(СНаг)аСО»вУ, -С(О0)Н88, -С(5)88, -С(О)М(Б8У)», -С( 5) M(VU)2, -OS(OM(VU)", -

ОС(О)НЯ, -С(О)М(ОВУ)АЯ, -С(МОНВ)АЯ, -5(0)288, -5(0)388, -502М(В)2, -5(0) H8, -MA?5BO2M(VU)", -

MA?5O»NV, -RI(IOHOVVU)", -OR(FOHO VU)", -R(FOHHOV 9)", -OR(OHOV'O)", -"SHCHONU)VU, -"SN-SNSO" Н, -С(-МН)-

M(VU)", and -"СНg)оМНО(О)НВВ; or two adjacent ВК" substituents on Ring A form a 5-6-membered ring that contains up to two heteroatoms as ring members; n represents, independently at each occurrence, 0, 1, 2,

Z, 4, 5, 6, 7 or 8; each t is independently chosen from such as: 1, 2, 3, 4, 5 and 6, and i represents 1, 2, 3, 4, 5, 6, 7 or 8.

In certain variants of the embodiment of such compounds Formula (I) or (1-A), one of K" and EK? represents NN; and the other of K" and EK" is chosen from such as: halogen, -"С(О)ОВ , -C(O)87, -C(O)M(A" 82), -M(B 82), -M(AU)", -

МНМА), -СН8, -СВТо, -ОСК8, "ОСА о, -587, -"СНа)О В, -(СНег)оВ", Si-Swalkyl, Si-Swheteroalkyl, Si-

Svhaloalkyl, Co-Svalkene, Co-Svalkyne, C--Svalkoxy group, C-Svalhaloalkyl group, aryl, heteroaryl,

C3-Swcycloalkyl, and C3-Swheterocycloalkyl, where each of the groups, such as: C1-Swalkyl, C1-Swheteroalkyl, C1-

C-haloalkyl, C-svalkene, C-svalkyne, C-svalkoxy, C:-Chaloalkyl, aryl, heteroaryl, C3-

Swcycloalkyl, and C3-Swheterocycloalkyl radical B" and KU, is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, -В87, -ОВ8, -С(О0)Н88, - OS(O)NV, -

С(ООНВВ, -М(ВУ)2, -Р(ФХХОВУ)», -OR(IFOHO VV)», -Р(IFOV 9)», -OR(IOHOV'O)», -С(О)М( VU)", -5(0)288, -

Z(O)2M(VU)", and -MA?5(O)2 HB.

In certain embodiments of such compounds of Formula (I) or (I-A), Ring A is phenyl, naphthyl, fluorenyl, indenyl, azulenyl, or anthracenyl, each of which is optionally substituted with 1-3 VA groups, in in which each KE" is independently selected from the following: -Н8, -В87, -ОВ", -ОНВ, -НО, -

OV, -588, -MO", -SM, -M(VU)2, -"MAS(O)H8, -MAUS(5)A8, -MAZS(OM(VU)", -MAZS(BUM(VAU) 2, -MA?SO»NV, -

MA?MA?S(O)NYA, /-MAZMAZS(O)M(VU)", -MAyaMAZSO»2NU, -С(0)С(О)Н88З, -С(О0)СН2С(О)НЯУ, - СО2Н88, 0 - (СНг)обО»вУ, -С(О)Н88, -С(5)88, -С(О)М(АУ)2, -С(5)М(8У)2, -ОС( O)M(VU)2, -OS(O)NYA, -S(OMOVUNU, -

С(МОВУ)АЯ, -5(0)288, -5(0)з388, -502М(АУ)2, -5(0)Н88, -МАЗ5О2М(ВУ)», -MA?5BO2gNYA, -P(IOHONU )»,

ОР(ОХОНВВ)», -Р(ФХОВ'О)», -ОР(ОМДОВ'О)», -МЩ(ОВУАЯУ -СН-СНСО»НУ, -С(-МН)-М(ВУ)», and - (CHg)oMne(O) HB In certain embodiments of such compounds of Formula (I) or (1-A), Ring A is phenyl or naphthyl.

In certain embodiments of such compounds of Formula (I) or (I-A), Ring A is benzofuranyl, benzofurazanyl, benzoxazolyl, benzopyranyl, benzthiazolyl, benzothienyl, benzazepinyl, benzimidazolyl, benzothiopyranyl, benzo(1,Z|dioxol, benzo|p |Ifuryl, benzoiB|hienyl, cinnolinyl, furazanyl, furyl, furopyridinyl, imidazolyl, indolyl, indolizinyl, indolin-2-one, indazolyl, |isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, 1,8-naphthyridinyl, oxazolyl, oxaiindolyl, oxadiazolyl, pyrazolyl, pyrrolyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, 4H-quinolizinyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl or tetrazolyl, each optionally substituted with 1-3 B" groups, where each B" is independently selected from such as: -B88, -87, -ОВ, -ОН8, -ВЙО, -ОВО, -5А8, -МО», -СМ, -М(ВУ) 2, -"MAZS(O)NU, -MAZS(5) 8, -"MAS(O)M(AU)", -

MAZS(5)IM(AU)", -MAYASO»VYA, -MAZMA?S(O)NYA, -MA"MAS(O)M(AU)", -MAyaMASO»VU, -S(O0)S(O )H88, -

С(О)СНоС(О)ВВ, -СО2Н88, -«(СНаг)аСО»вУ, -С(О0)Н88, -С(5)88, -С(О)М(Б8У)», -С( 5) M(VU)2, -OS(OM(VU)", -

ОС(О)НЯ, -С(О)М(ОВУ)АЯ, -С(МОНВ)АЯ, -5(0)288, -5(0)388, -502М(В)2, -5(0) H8, -MA?5BO2M(VU)", -

MAO», -Р(ІОХО ВВ)», -Р(ИФОХО НУ)», -Р(ФХОН 9)», -Р(ОХО ВО)», -ШЧО НВ, -"СН-СНСО»НУ, -С( -MN)-

M(VU)2, and -"СНе)оМНО(О)А8. In certain embodiments of such compounds of Formula (I) or (I-A), Ring A is pyridyl, benzo|1,3|dioxole, thienyl, benzothienyl, benzofuranyl, or indolyl.

In certain embodiments of the compounds of Formula (I) and Formula (1-A), the compounds have the structure of Formula (X-A):

IS! хх их - оз в ве:

And oh

E M a lot

Formula (X-A).

In certain embodiments of the compounds of Formula (I) or Formula (I-A), the compounds have a structure

Formulas (XI):

VA

From in

VM

MH,

Formula (XI).

In certain embodiments of compounds of Formula (I) or Formula (I-A), the compound has the structure of Formula (XII) or Formula (XIII): kA v » cha | chu 2 MA Ohm

E M and M

Mn, Mn,

Formula (XII) Formula (XP)

In certain embodiments of such compounds Formula (I) or (I-A), Formula (X-A) and (XI) - (XIII), B" and Co are independently selected from such as: H, halogen, -C(O )ОВ, -С(О)8, -С(О)М(А" 82), -М(АВ 2), -М(AZ)», -

MNMA)", -SA8, -SVTo, -OS8, -OSAT, -5587,. -"СНа)ав", -"(СНг)ООВ, -С1-SvAlkyl, Si-Svhaloalkyl, Se-

Svalken, Cg-Svalkin and C-Svalcoxy group, where each of the groups such as: C-Svalkyl, C-Svhaloalkyl, Cg2-

Svalken, Co-Svalkin and Si-Svalcoxy radical group BK" and KK" is optionally substituted with 1-3 substituents independently selected from such as: halogen, -CM, -B", -OH8, -C (O)NO, -

ОС(О)Н8, -С(О)ОНВВ, -М(ВУ)2, -Р(ИОХОВУ)», -OR(IFHONVU)», -Р(IFHOV З)», -OR(ОХОВ'О)» . ),

Formula (X-A) and (XI) - (XII), B" and EK? are independently chosen from such as: H, halogen, -С(О)ОВ, -С(О)В, -

С(О)М(А" В), -М(В 82), -М(ВУ)2, -"МНМ(ВУ)", -И АВ, -СВТО, -ОС8, -ОС о, -587, -««"SNa)pOVU, -«(SNag) av, -

C-Swalalkyl, C-Swhaloalkyl, Co-Swalkene, Co-Swalkene and C-Swalcoxy group wherein each of the groups such as:-

Ci-Svalkyl, Ci-Svhaloalkyl, Co-Svalkene, Co-Svalkin and Si-Svalcoxy group, is optionally substituted with B.

In certain embodiments of the compounds of Formula (I) and Formula (1-A), the compounds have the structure of the Formula (XIM): and A 1 then 0-3 and M:

Residential complex M

E M

MH,

Formula (CHEM).

In certain variants of the embodiment of such compounds Formula (CHEM) B" is chosen from such as H, halogen, -

СОН, -ФС(О0Н8, -С(О)М(А"В2), -М(А TV 2), -587, -«(СНа)зпВ7, -««СНа)зОвВ, -С1-Svalkil, Si -Swhaloalkyl,

C2-Swalkene, Cg-Swalkene and C-Swalkoxy group, where each of the groups such as: C-Swalkyl, C-Swhaloalkyl, Cg2-

Svalken, Sg-Svalkin and Si-Svalcoxy radical group K" and KU, optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, -В87, -ОВ8, -С(О )H8, -

ОС(О)Н, -С(О0)ОН8 -М(ВУ)2, -Р(ИОХОВУ)2, -OR(ХОХОНВУ)», -Р(ИХОВ 9)», -OR(IOHOV'О)» -С(О)М(ВУ)", - (0288, -5(0)2 М(ВУ)2, and -МНБ(О)2НА. In other variants of the embodiment of such compounds Formula (ХМ), К" is chosen from such as H, halogen, -"С(О)ОВ, -С(О0)8", -С(О)М(АА), MAА2), -587, -"СНа)ОВ", - ( CHn)α7, -C1-Swalkyl, C1-Swhaloalkyl, Co-Swalkene, Cs-Swalkyne and Cs-Swallowoxy group, where each of the groups such as: -Ci-Swalkyl, C1-Swhaloalkyl, Co-Swalkene, Co- Svalkin and Si-Svalcoxy group is optionally substituted by K/.

In certain variants of the embodiment of such compounds Formula (I) or (I-A), Formula (X-A) and (XI) - (XIM), B" is selected from such as: H, C:i-alkyl, aryl, heteroaryl , C3-Swcycloalkyl, and C3-Swheterocycloalkyl, where each of the groups, such as: C1-Swalkyl, aryl, heteroaryl, C3-Swcycloalkyl and C3-Swheterocycloalkyl of the K7 radical, is optionally substituted with 1-3 B"C groups and each short circuit is independently selected from such as: halogen, -SM, -I VU, -HOV, -OSC8, -Г ATO, - ОВ, -ОГ о, -И 88, - ОН, -ОГ 8, -И 588, - And 58, -

IS(O)NYA, -OS(O)H8, - S(O)OVYA, - S(O)B8Ya, - OS(O)ONB8, - S(O)MAYAV", - S(O)MA?AU , -I (VU), -

ГМмАУА8, -МАУАТО, - С(О)М(АУ)», - 5(О)2А8, -И (ОН, - С(О)MAVON, -МАС(О)ВВ, -ГМАС(ООНВ, -

I 5(O)2M(AU)2, -01 5(0)2M(8U)", -IMAZB(O)2A8, - S(O)MARI M(VU)", -GRIOHOVU)", - ORIOHOVU) ", -

GR(IOHOV' 9)" and -OYI RIOHOV'9)".

In certain variants of the embodiment of such compounds Formula (I) or (I-A), Formula (X-A) and (XI) - (XIM), B" is selected from such as: H, C:i-alkyl, aryl, heteroaryl , C3-Swcycloalkyl, and C3-Swheterocycloalkyl, where each of the groups, such as: C1-Swalkyl, aryl, heteroaryl, C3-Swcycloalkyl, and C3-Swheterocycloalkyl, is optionally substituted with 1-3 B"C groups and each KZ is independently chosen from such as: halogen, C-Svhaloalkyl, I 8, I VU, -HOV8 and -OIII 8.

In certain embodiments of compounds of Formula (I) or (1-A), Formula (X-A) and (XI) - (KHIM), have the structure of Formula (KHM) or Formula (KHMI): (803 (vd BA and / 2nd - In the lake

Ж чу х Ж a: - YAM | - l vi M v M

MN. Mn,

Formula (ХУ) Formula (ХМИ).

In certain variants of the embodiment of such compounds Formula (I) or (I1-A), Formula (X-A) and (XI) - (HMI), VZ is chosen from such as: -I VU, -Г ОВ, -ОЙ КУ, - 8/9, -H OV, -OG o, -I 88, -HON8, -OG KU, -I AB, -I 589, -

IS(O)NYA, -OS(O)H8, - S(O)OVYA, - S(O)B8Ya, - OS(O)ONB8, - S(O)MAYAV", - S(O)MA?AU , -I (VU), -

MA, -MA?VO, - С(О)М(AZ)», -И5(О0)2Н88, -И 5(0)88, - С(О)МAZON, -МАЗС(О)ВУ, - MAZS( UNO, -

I 5(O)2M(AU)2, -01 5(0)2M(8U)", -IMAZB(O)2A8, - S(O)MARI M(VU)", -GRIOHOVU)", - ORIOHOVU) ", -

GR(IOHOV' 9)" and -OYI RIOHOV'9)".

In certain embodiments of such compounds of Formula (I) or (I-A), Formula (X-A) and (Xi) - (XMI), IV'o is aryl or heteroaryl, where the aryl and heteroaryl groups are optional substituted with 1-3 substituents selected from such as: halogen, -H8, -ОВ8, and -М(ВУ)".

In certain embodiments of such compounds Formula (I) or (I-A) Formula (X-A) and (Xi) - (XMI), B" is phenyl, optionally substituted with 1-3 substituents that choose from such as: halogen, -B8, -OH, and -"M(VU)".

In certain embodiments of such compounds of Formula (I) or (I-A), Formula (X-A) and (XI) - (HMI), 88 is selected from such as: H, C-Salkyl and C-Swihaloalkyl. In certain variants of the embodiment of compounds Formula

XII, XIM, XM or XMI, the compound is selected from the following: 2-(4-(2-(5-amino-Y-methylbenzo CHY, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)propane-2 -ol;. 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo CHY, 7|naphthyridin-5-amine; 2-(2.4-dimethylphenethyl)-benzo CI, 7|Inaphthyridin-5-amine; ethyl 4-(2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 2-(4-Dimethylamino)phenethyl)-8-methylbenzol, 7|Naphthyridin-5-amine, and 2-(4-methoxyphenethyl)-8-methylbenzol/1,7Naphthyridin-5-amine. Each of these compounds separately includes a preferred embodiment of the compounds, compositions, and methods disclosed herein.

In certain embodiments of the compounds, compositions, and methods disclosed herein, the compound

Formula (I) is selected from the following: 2-methylbenzoic acid, 7|Inaphthyridin-5-amine; 2-propylbenzo(SHI, 7|naphthyridin-5-amine; 2- ethylbenzo DP, 7Inaphthyridin-5-amine; / 2-(3-«(trifluoromethyl)phenethyl)benzo| 1, 7|Inaphthyridin-5-amine; 2 - (2,4-difluorophenethyl)benzo DI, 7|naphthyridin-5-amine; 2-(3-methoxyphenethyl)-benzoxyl,7|naphthyridin-5-amine; 8-methylbenzoxyl, 7-naphthyridin-5-amine; 8- methyl-2-phenethylbenzo|DI, 7|naphthyridine-5-amine; methyl 5-aminobenzo|D(1,7|Inaphthyridine-Z-carboxylate; 5-amino-M-methylbenzo Shchy, 7|naphthyridine-3-carboxamide; (5-aminobenzoxy, 7U|Inaphthyridin-3-yl)methanol; 8-phenylbenzo|ХХ1,7|naphthyridin-5-amine; 3-(ethoxymethyl)benzo DP, 7|Inaphthyridin-5-amine; benzoХХХХХ1,7Inaphthyridin- 3,5-diamine; benzo SCI, 7Inaphthyridin-5-amine; methyl 5-aminobenzoSCI, 7|naphthyridine-8-carboxylate; 5-aminobenzo|CI, 7UInaphtiridine-8-carboxylic acid; ethyl 5-aminobenzo|(DI1,7 |naphthyridine-8-carboxylate; (5-aminobenzo ХІ, 7|naphthyridin-8-yl)methanol; 5-aminobenzo|(ДІ1,7|naphthyridine-3-carboxylic acid; 5-aminobenzo ДІ, 7|naphthyridin-3- carbaldehyde; 2-(2-methylphenethyl)benzo|D(I1,7UInaphthyridin-5-amine; ylphenethyl)benzo|D(1,7|naphthyridin-5-amine; 2-(4-methylphenethyl)benzo|DI1,7|Inaphthyridin-5-amine; 8-chlorobenzo SHIE, 7-Naphthyridin-5-amine; ethyl 5-

aminobenzo| 11, 7UInaphthyridine-9-carboxylate; 8-methoxybenzo| 1, 7)|Inaphthyridin-5-amine; 8-(methylsulfonyl)benzo|DI1,7|naphthyridin-5-amine; 8-(trifluoromethyl)-benzoDI1, 7|naphthyridin-5-amine; 8-fluorobenzoic acid, 7/|Inaphthyridin-5-amine; 3-Methoxy-benzo SHIE, 7|Inaphthyridin-5-amine; 3-butoxybenzo|C1, YInaphthyridin-5-amine; 3-(benzyloxy)benzo| DY, 7UInaphthyridin-5-amine; 3- methylbenzo SHI, 7|Inaphthyridin-5-amine; 3-chlorobenzo(/1,7|naphthyridine-5-amine; M3,M3- dimethylbenzo DY, 7|Inaphthyridine-3,5-diamine; M3-butylbenzo CHIP, 7Inaphthyridine-3,5-diamine; 3-vinylbenzo DP, 7-Naphthyridin-5-amine; 3-ethylbenzo|CI, 7|Naphthyridin-5-amine; 3- fluorobenzo ZHI, 7/|Naphthyridin-5-amine; 2-phenethylbenzo|C1, YInaphthyridin-5-amine; 8-methyl- 2-(2-(naphthalen-1-yl)uethyl)benzo|(DI1,7|naphthyridin-5-amine; 8-methyl-2-(2-(naphthalen-2-yl)/'ethyl)ubenzo SHI, 7|Naphthyridin-5-amine; 4-(2-(5-amino-8-methylbenzo DI, 7|Naphthyridin-2-yl)/ethyl)benzoic acid; 3-(2-(5-amino-8 -methyl-benzo|DI1,7|naphthyridin-2-yl)ethyl)benzoic acid; 2-(3-chlorophenethyl)-8-methyl-benzo|SHI, 7UInaphthyridin-5-amine; 2-(2-chlorophenethyl)- 8-methylbenzo ХІ, 7|Inaphthyridin-5-amine; (3-(2-(5-amino-8-methylbenzo| Х1, 7UInaphthyridin-2-yl)ethyluphenyl)methanol; 2-(4-chlorophenethyl)-8- methylbenzo|C(1,7|naphthyridin-5-amine; 2-(4-butylphenethyl)benzo|D(1,7|naphthyridin-5-amine;. 2-(4-butylphenethyl)-8-methylbenzo|ЦІ1, Naphthyridin-5-amine; 2-(4-propylphenethyl)-benzo|CI1, Y Naphthyridin-5-amine; 2-(4-(trifluoromethyl)f enethyl)benzo| SHI, 7-Naphthyridin-5-amine; 2-(2,5-dimethylphenethyl)-8-methylbenzo H/1,7|Inaphthyridin-5-amine; 8-methyl-2-(4-propyl-phenethyl)benzo| DY, 7|Inaphthyridin-5-amine; 8- methyl-2-(2,4,5-trimethylphenethyl)-benzo|ЦІ1, 7|Inaphthyridin-5-amine; 2-(2,5- dimethylphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-isopropylphenethyl)-8-methylbenzol/1,7|Inaphthyridin-5-amine; 2-(4-heptylphenethyl)-8-methyl-benzo CI, 7|naphthyridin-5-amine; 2-(4-isobutoxyphenethyl)-8-methylbenzo|DC(I1,7|naphthyridin-5-amine; 2-(4-(2-methoxyethoxy)methoxy)phenethyl)-8-methylbenzo| 1, 7UInaphthyridin-5-amine; 8-methyl-2-(4-(2- phenoxyethoxy)phenethyl)benzo SHI, 7|Inaphthyridin-5-amine; 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)phenethyl)-8-methylbenzo| DY, 7|naphthyridine-5-amine; 8-methyl-2-(4-(4-phenylbutoxy)phenethyl)benzo|C1, 7|Inaphthyridin-5-amine; 2-(4-(allyloxy)phenethyl)-8-methylbenzo SHI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(3-phenylpropoxy)phenethyl)-benzo DP, 7-Naphthyridin-5-amine; 2-(4-(heptan-4-yloxy)phenethyl)-8-methyl-benzo|(І1,7|naphthyridin-5-amine; 8-methyl-2-(4-(4-methylpent-3-enyloxy) uphenethyl)-benzo|/1,7|naphthyridin-5-amine; 2-(4-(2-cyclohexylethoxy)phenethyl)-8-methyl-benzo| DI, 7|inaphthyridin-5-amine; 2-(4- isopropoxyphenethyl)-8-methylbenzo DI, 7|naphthyridin-5-amine; 2-(4-(3,3-dimethylbutoxy)phenethyl)-8-methylbenzo ХІ, 7|Inaphthyridin-5-amine; 2-(4-( 2-(tert-butyldimethylsilyloxy)ethoxy)-2-methylphenethyl)-8-methylbenzo|DI, 7|naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(4- (dimethylamino)phenethyl)benzo CH, 7|naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(2,4- dimethylphenethyl)benzo SHI 7|naphthyridin-5-amine; /-M-(4-(2-(5-amino- I-methylbenzo CY, 7|naphthyridin-2-yl)/ethylphenyl)acetamide; M-(4-(2-(5-amino-benzo DY, 7|naphthyridin-2-yl)ethyl)phenyl)acetamide; M- (4-(2-(5-amino-8-methyl-benzoD/1,7|naphthyridin-2-yl)ethyl)phenyl)-4-methylbenzenesulfonamide; 3-methyl-9-p-tolyl-9,10- dihydrobenzo|Cfuroi2,3-5111,7|naphthyridine-b-amine; 4-(2-(5-amino-8-methyl-benzo DP, 7UInaphthyridin-2-yl)ethyl)-3-methylbenzoni trill; 4-(2-(5-amino-8-methyl- benzol, 7|Inaphthyridin-2-yl)ethyl)-M-(2-aminoethyl)-3-methylbenzamide; 8-methyl-2-(2-methyl-4-(1H-tetrazol-5-ylophenethyl)benzo DP, 7|Inaphthyridin-5-amine; methyl 2-(4-(2-(5-amino-8- methylbenzo Ш/1,7|Naphthyridin-2-yl)ethyl)-3-methylbenzamido)-4-methylpentanoate; methyl 2-(4-(2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2- yl)ethyl)-3-methylbenzamido)acetate; 2-(4-(2-(5-amino-8-methylbenzol/1,7|inaphthyridin-2-yl)ethyl)-3-methylbenzamido)-4-methylpentanoic acid; /2-(4-(2-(5-amino-8-methylbenzo ЧИ, 7|Inaftyridin-2-yl)ethyl)-3-methylbenzamido)acetic acid; /6-(5-amino-8-methylbenzo C1,7|Naphthyridin-2-yl)hexan-1-ol; 7-(5-amino-8-methylbenzo|D(1,7|Naphthyridin-2-yl)heptanoic acid; 11-(5-amino-8-methyl -benzoS/I1, 7YInaphthyridin-2-ylundecan-1-ol; ethyl 2-(4-(2-(5-amino-8-methyl-benzo DI, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy )acetate; 2-(4-(2-(5-amino-8-methyl-benzo DP, 7-Naphthyridin-2-yl)ethyl)-3-methylphenoxy)acetic acid; 3-(4-(2-(5- amino-8-methyl-benzo IP, 7-Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propanoic acid; 6-(4-(2-(5-amino-8-methylbenzo CI1,7|Inaphthyridin-2-yl) )ethyl)-3 -methylphenoxy)caproic acid; 8-methyl-2-(2-methyl-4-(methylthio)phenethyl)benzo DP, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(methylsulfonyl)/phenethyl)benzo| DY, 7|Inaphthyridin-5-amine; 2-(4-(hexyloxy)phenethyl)-8-methylbenzo SHHI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-phenethoxyphenethyl)-benzo|CI1, 7-Inaphthyridin-5-amine; 8-methyl-2-(4-«(pentyloxy)phenethyl)benzo CY, 7-Naphthyridin-5-amine; 8-methyl-2-(4-(4-methylpentyloxy)phenethyl)benzo|C1, 7-Naphthyridin-5-amine; 2-(2-fluorophenethyl)benzo|ЦІ1, 7ІNaphthyridin-5-amine; 2-(3-Fluorophenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-fluorophenethyl)benzo|ЦІ1, YInaphthyridin-5-amine; /2-(2-(thiophen-3-yl)ethyl)-benzo| DY, 7|naphthyridine-5-amine; (5-aminobenzoic acid, 7|naphthyridin-2-yl)methanol; 2-(3,4-dimethylphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(3,4-dimethylphenethyl)-8-methyl-benzo SHII, 7|Inaphthyridin-5-amine; 2-(3,5-Dimethylphenethyl)-8-methylbenzo SH, 7|Inaphthyridin-5-amine; /2-(2-(benzofuran-5-yl)ethyl)-8-methylbenzo CI, 7-Naphthyridin-5-amine; 8-methyl-2-(2-nitroethyl)benzo CHIP, 7|Inaphthyridin-5-amine; 2-(aminomethyl)-8-

methylbenzo SH, 7|Inaphthyridin-5-amine; M2,b8-dimethylbenzo CY, 7|naphthyridine-2,5-diamine; 2-(5-amino-8-methyl-benzo|D/1,7|naphthyridin-2-yl)-1-phenylethanol; 2-(5-amino-8-methylbenzo(C1,7|naphthyridin-2-yl)-1-(4-methoxyphenyl)ethanol; 2-(biphenyl-2-yl)y-Y-methylbenzo DP, 7Inaphthyridin-5 -amine; 2-(2-(2,6- dimethylpyridin-3-yl/ethyl)-8-methylbenzo CY, 7|naphthyridin-5-amine; /2-(2-(5-methoxypyridin-2-yl) ethyl)-8-methylbenzo|DI,7|naphthyridin-5-amine; 3-(4-(2-(5-amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)ethyl)phenyl)propanoic acid 5-(2-(5-amino-8-methylbenzo| 1, 7-Naphthyridin-2-yl)ethyl)-4-methylpyridin-2(1H)-one; 6-(2-(5-amino-8-methyl) -benzo(DI, 7|naphthyridin-2-yl)ethyl)pyridin-3-ol; 8-methyl-2-(4-(trifluoromethoxy)-phenethyl)-benzo| 1, 7|naphthyridin-5-amine; 2 -(2-(2,3-dihydro-1H-inden-5-yl)ethyl)-8-methyl-benzo|DI1,7|naphthyridin-5-amine; 2-(2-(2,3-dihydro -1 H-inden-5-yl)/ethyl)/benzo D(1,7|naphthy-ridin-

B-amine; (E)-3-(4-(2-(5-amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)ethyl)-3-methylphenyl)-acrylic acid; (E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|C1, 7YInaphthyridin-8-yl acrylate; 8-(prop-1-en-2-ylbenzo DP, 7|Inaphthyridine -5-amine; 5-aminobenzo|D(Y1,7Inaphthyridin-8-carbonitrile; (E)-8-(3-methylbut-1-enyl)benzo|ЦЙ1,7UInaphthyridin-5-amine; 8-(2 -methylprop-1-enyl)ubenzo 1,7Naphthyridin-5-amine; (E)-8-(pent-1-enyl)u-benzoShP,7|naphthyridin-5-amine; (E)-8-styrylbenzo|DY . (2-cyclopropylvinyl)/benzo|(D(І1,7ІNaphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-phenethylbenzo|І1,7ІNaphthyridin-5-amine; 9-phenethylpyrido|1,2-с|/ 11,7|Inaphthyridine-b-amine; methyl 5-amino-2-(4-methoxyphenethyl)benzo TSI, 7|Inaphthyridine-8-carboxylate; 8-nitrobenzo|DI1,7|naphthyridine-5-amine; Z-chloro -8-methylbenzo|ЦІ1, ІNaphthyridin-5-amine; methyl 5-amino-Z-chlorobenzo|ІІ1, 7ІNaphthyridine-8-carboxylate; methyl 5-amino-3-fluorobenzo( ДІ, 7|naphthyridine-8-carboxylate; Z -chloro-8-nitrobenzo OR, 7|Inaphthyridin-5-amine; . (5-amino-3-chlorobenzo|1, 7|Inaphthyridin-8-yl)umethanol; (5-amino-2-phenethyl-benzo|DY, 7-Naphthyridin-8-yl)methanol; 4-(2-(5-amino-8-fluorobenzo DP, 7|Inaphthyridin-2-yl)/ethyl)benzaldehyde; 2-(4-(2-(5-amino-8-fluorobenzo DY, 7-Inaphthyridin-2-yl)ethyl)benzyl-amino)ethanol; 3-(4-(2-(5-amino-8-fluorobenzoic acid, Ianaphthyridin-2-yl)ethyl)benzylamino)propan-1-ol; 8-fluoro-2-(4-(2-methoxyethylamino)methyl)phenethyl)benzo| DI, YInaphthyridin-5-amine; (5-amino-2-(4-methoxy-2-methylphenethyl)benzo|D(I1,7|Naftyridin-8-yl)umethanol; 3-(2-(5-aminobenzo|DI1,7|naphthyridin-2- yl)ethylphenol; 2-(2-methoxyphenethyl)benzo|DI1,7|naphthyridine-5-amine; 2-(4-ethylphenethyl)benzo CH, 7|Inaphthyridin-5-amine; / 2-(4-ethylphenethyl) )-8-methylbenzo|ЦІ1,7|naphthyridine-5-amine; 2-(4-(dimethylamino)phenethyl)benzo CH, 7|Inaphthyridin-5-amine; 2-(4-(piperidin-1-ylphenethyl)benzo |DI1,7|naphthyridin-5-amine; 2-(4-tert-butylphenethyl)-8-methylbenzo

B-amine; 8-methyl-2-(4-(piperidin-1-yl)y-phenethyl)benzo|SHI1, 7YInaphthyridin-5-amine;. 2-(4-Methoxyphenethyl)-8-methyl-benzo|DI1,7|naphthyridin-5-amine;. 2-(3,5-dimethoxyphenethyl)-8-methylbenzo|CI1, 7-Naphthyridin-5-amine; 8-methyl-2-(2-"-trifluoromethyl)phenethyl)benzo CHY, 7U|Inaphthyridin-5-amine; 4-(2-(5-amino-8-methylbenzo ХІ, 7|Inaftyridin-2-yl)ethyl)-M-hydroxybenzimidamide; 4-(2-(5-amino-8-methyl-benzoSHI, 7|naphthyridin-2-yl)ethyl)benzonitrile; 8-methyl-2-(4-(1-morpholinoethyl)phenethyl)-benzo DP, 7-Naphthyridin-5-amine;. 2-(4-aminophenethyl)-8-methylbenzo|DI1,7|naphthyridin-5-amine; 1-(4-(2-(5-amino-8-methylbenzo CH, 7|Inaphthyridin-2-yl)ethyl)phenyl)guanidine; 8-methyl-2-(4-(1- (phenethylamino)ethyl/phenethyl)benzo CI, 7|Inaphthyridin-5-amine; 2-(4-(2-(5-amino-8- methylbenzoSHII1,7|Inaphthyridin) -2-yl)ethyl)phenyl)acetonitrile; 2-(4-(piperidin-1-ylmethyl)-phenethyl)benzo, 7|naphthyridin-5-amine; 1-(4-(2-(5-aminobenzo) . benzo|DI, 7|naphthyridin-5-amine; 2-(4-(2-aminopropan-2-yl phenethyl)benzo|DI, 7|naphthyridin-5-amine; 1-(1-(4-(2-( 5-aminobenzo CHY, 7|Inaphthyridin-2-yl)/ethylphenyl)ethyl)pyrrolidine-3-carboxylic acid; 8-methyl-2-(4-(1-(phenylamino)ethyl)-phenethyl)benzo Cchy, 7| naphthyridine-5-amine; 2-ethyl-8-methylbenzo ЦІ, 7|Inaphthyridin-5-amine; (5-amino-8-methylbenzo Х/1,7|Inaphthyridin-2-ylmethanol; 8-methyl-2-propylbenzo | SHІ, 7|Inaphthyridin-5-amine; /-2-(2-(1H-indol-5-yl)ethyl)-8-methylbenzo CI, 7|Inaphthyridin-5-amine; 2-(4- ethoxyphenethyl)-8-methylbenzo ХИ1,7|Inaphthyridin-5-amine; 8-methyl-2-(4-phenoxyphenethyl)-benzog(PCІ1,7|naphthyridin-5-amine; 2-(2, 4-dimethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; 2-(2,4-dimethylphenethyl)-8-methylbenzo Х/1,7|Inaphthyridin-5-amine;. 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo CH, 7|naphthyridine-

B-amine; 4-(2-(5-amino-8-methylbenzopyridine, 7-inaphthyridin-2-yl)ethyl)-3-methylphenol; 2-(2-(2,3- dihydrobenzofuran-5-yl)ethyl)-8-methyl-benzo DI, 7|naphthyridin-5-amine; 2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethanol; 3-methyl-9-phenyl-9,10-dihydrobenzo|Pfuroi|2,3-

BI, 7|Inaphthyridin-6-amine; 8-methylbenzo DI, 7|naphthyridine-2,5-diamine; 1-(5-amino-8-methylbenzo-1,7-inaphthyridin-2-yl)upropan-2-ol; 2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)acetonitrile; M-(5-amino-d8-methylbenzo|11,7|naphthyridin-2-yl)acetamide; 2-(5-amino-8-methylbenzo CII1,7|Inaphthyridin-2-yl)-1-(2,4-dimethylphenyl)ethanol; 2-(2-(6-Methoxy-4-methylpyridin-3-yl)ethyl)-8-methyl-benzo DI, 7-Naphthyridin-5-amine; 4-(4-(2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)ethyl)-phenyl)butan-1-ol; methyl 3-(4-(2-(5-amino-8-methylbenzo|D(/1,7|naphthyridin-2-yl)ethyl)phenyl)-propanoate; 3-(4-(2-(5-amino -8-methylbenzo CI, 7-Naphthyridin-2-yl)ethylphenyl)propan-1-ol; 4-(4-(2-(5-amino-8-methylbenzo CI, 7|Naphthyridin-2-yl)ethyl)phenyl) -2-methylbutan-2-ol; 2-(4-(aminomethyl)phenethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine; (E)-ethyl 3-(4-(2-(5-amino) -8-

methylbenzo ХІ/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate; ethyl 3-(4-(2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)propanoate; 2-(4-(2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzyl)propane-1,3-diol; 3-(4-(2-(5-amino-8-methylbenzol/1,7|inaphthyridin-2-yl)ethyl)-3-methylphenylpropanoic acid; 5-amino-2-(4-methoxy-2-methylphenethyl) )benzo|D(I1,7Inaphthyridin-8-carbaldehyde; ethyl 4-(2-(5-amino-8- methylbenzoSHII1,7|Inaphthyridin-2-yl)ethyl)benzoate; 8-methyl-2-(4-methylphenethyl )- benzo DP, 7UInaphthyridin-5-amine; 2-(4-(2-(5-amino-8-methylbenzo| DI, 7|Inaphthyridin-2-yl)ethyl)-phenyl)propan-2-ol; ( 4-(2-(5-amino-8-methylbenzo C(1,7|naphthyridin-2-yl)ethylphenyl)methanol; ethyl 4-(2-(5-amino-8-methylbenzo|DI, 7|Inaphthyridin- 2-yl)ethyl)-33-methylbenzoate; 4-(2-(5-amino-8-methylbenzo H1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoic acid; (4-(2-(5 -amino-8- methylbenzo 1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)methanol; 8-methyl-2-(2,4,6-trimethyl-phenethyl)benzo|D(1,7| naphthyridin-5-amine; 2-(4-propoxyphenethyl)benzo ХІ, 7|Inaphthyridin-5-amine; / (E)-3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|ЦІ1, YInaphthyridin-8-ylloacryl acid; yl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|PC1, 7|Inaphthyridin-8-yl)/propanoate; 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|D(1,7Inaphtyridin-8-yl/upropanoic acid; 3-(5-amino-2-(4-methoxy-2-methylphenethyl) )benzo|D(1, 7Inaphthyridin-8-ylpropan-i-ol; 5-aminobenzo ХІ1,7|Inaphthyridin-8-ol; /-5- aminobenzo| ЦІ, 7UInaphthyridin-8-carbaldehyde; 1-(5-aminobenzo SH, 7|Naphthyridin-8-yl)ethanol; - 1-(5-amino-benzo(DI1,7Я|naphthyridin-β8-yl)ethanone; 8-isopropylbenzo|ХЙ1,7|naphthyridin-5-amine; 8- vinyl-benzo DP, 7UInaphthyridin-5-amine; 8-ethylbenzo|ЦІ1, 7ІInaphthyridin-5-amine; 8-(methoxymethyl)-benzo DP, 7U|Inaphthyridin-5-amine; (5-amino-2-(4- methoxyphenethyl)benzo|DY, 7|Inaphthyridin-8-yl)methanol; benzo IP, 7UInaphthyridin-5,8-diamine; 8-(aminomethyl)benzo|DY, 7|naphthyridin-5-amine; 3-fluoro-8- methylbenzo SHI, 7|Inaphthyridin-5-amine; (5-amino-3-fluorobenzo| DI, 7|naphthyridin-8-yl)methanol; 3-chlorobenzo SHI, 7|Inaphthyridine-5,8-diamine; C -fluoro-benzo DY, 7-naphthyridine-5,8-diamine; 8-isobutylbenzo DP, 7-Inaphthyridin-5-amine; (E)-8-(prop-1-enyl/ubenzo|(DY1,7|naphthyridine-5-amine 8-propylbenzoic acid, 7U|Inaphthyridine-5-amine ; 8-(2-cyclopropylethyl)benzo CH, 7|Inaphthyridin-5-amine; 8-phenethylbenzo|C1, 7UInaphthyridin-5-amine; (5-amino-2-(4-bromophenethyl)benzo| SHI, 7UInaphthyridin-8-ylmethanol; (5-amino-2-(4-methoxy-2-methylphenethyl)benzo|D1,7|naphthyridin-8-yl) methanol; 2-(4-methoxy-2-methylphenethyl)-8-pentylbenzo|DI, 7|naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(4-methoxy-2-methylphenethyl)benzo|C1 . benzo DP, 7|Naphthyridin-8-ylmethanol; (2-(2-(1H-indol-5-yl)ethyl)-5-aminobenzo(DSHI1,7|naphthyridin-v-yl)umethanol; methyl 4- (2-(5-amino-8-methylbenzo TSI, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 4-(2-(5-amino-8-methylbenzo Х/1,7|Inaphthyridin-2 -yl)ethyl)-N,3-dimethylbenzamide; 4-(2-(5-amino-8- methylbenzo ХІ, 7|Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide; 2-(4- methoxyphenethyl) benzo TSI, 7|Inaphthyridin-5-amine; 2-(4-methoxy-2-methylphenethyl)-benzo DP, 7UInaphthyridin-5-amine; 4-(2-(5-amino-8-meth) ylbenzo (1,7 |naphthyridin-2-yl)ethyl)-3-methylbenzamide; 4-(2-(5-amino-3-methylbenzo 1, 7|Inaphthyridin-2-yl)ethyl)-M, M,3-trimethylbenzamide; 4-(2-(5-amino-8-methylbenzo|DP, 7|Inaphthyridin-2-yl)ethyl)-M-(2-hydroxyethyl)-3-methylbenzamide; 4-(2-(5-amino-8-methylbenzo CH, 7|Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-3-methylbenzamide; (4-(2-(5-amino-8-methylbenzo ЧИ, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl) (pyrrolidin-1-yl)umethanone; 4-(2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)-N-(2-(diethylamino)ethyl)-3-methylbenzamide; (4-(2-(5-amino-8-methyl-benzo|D/1,7|naphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazin-1-yl)umethanone; (4-(2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)(piperazin-1-yl)methanone; 4-(2-(5-amino-8-methylbenzo H1,7|Inaphthyridin-2-yl)ethyl)-3-methyl-N-(2-(pyrrolidin-1-yl)ethyl)-benzamide; 4-(2-(5-aminobenzo|CI, 7-Naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide; //-4-(2-(5-amino-8-methylbenzo CH, 7|Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M-methylbenzamide; 2-(4-(2- (5-aminobenzo(SHI, 7naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol; 2-(4-butoxyphenethyl)-8- methylbenzo SHI, 7|Inaphthyridine -5-amine; 2-(2-(biphenyl-4-yl)ethyl)-8-methylbenzo DI, 7|naphthyridin-5-amine; 2-(1,3-dihydroisobenzofuran-1-ylylmethyl)-8-methylbenzo ЦИ, 7Inaphthyridin-5-amine; 8-methyl-2-(4-(2-methylallyloxy)phenethyl)-benzogPSHI1, 7|Inaphthyridin-5-amine; 2-(4-(isopentyloxy)phenethyl)-8-methyl- benzo DP, 7UInaphthyridin-5-amine; 4-(2-(5-amino-B8-methylbenzo DY, 7|naphthyridin-2-yl)/'ethyluphenylpropyl carbonate; ethyl 5-(4-(2-(5-amino- 8-Methylbenzo CY, 7Naphthyridin-2-yl)/'ethylphenoxy)pentanoate; 2-(4-(cyclopentyloxy)phenethyl)-8-methyl-benzo|CY1, YInaphthyridin-5-amine; 2-(4-(cyclobutylmethoxy) phenethyl)-8-methyl-benzo|(PCI1,7|Inaphthyridin-5-amine; 8-methyl-2-(4-(2-morpholinoethoxy)phenethyl)-benzog (1,7UInaphthyridin-5-amine; 2-( 4-(2-(5-amino-8-methylbenzo ХІ1,7|Inaphthyridin-2-yl)ethylphenoxy)-1-phenylethanone; 5-(4-(2-(5-amino-8-methylbenzo ІІ1,7| Inaphthyridin-2-yl)uethylphenoxy)pentanoic acid; 2-(4-(2-(5-amino-8-methyl) lbenzo ЩХ1,7|Inaftyridin-2-yl)uethylufenoxy)ethanol; 2-(4-(2-(5-amino-8- methylbenzo Х/1,7|Inaphthyridin-2-ylluethylufenoxy)-M, M-dimethylacetamide; 8-methyl-2-(2-methyl-4-(2 - morpholinoethoxy)phenethyl)-benzo 1, 7|naphthyridin-5-amine; 2-(2-(4-(2-(5-amino-8-

methylbenzo (1,7-inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethanol; diethyl 3-(4-(2-(5-amino-8-methyl-benzo|D/1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate; 3-(4-(2-(5-amino-8-methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonic acid; 2-(4-butoxy-2-methylphenethyl)-8-methylbenzo DCP, 7-Naphthyridin-5-amine; 2-(4-(2-(5-amino-benzo-SHI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 2-(2-(4-(2-(5-amino-benzo-CH, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethanol; ethyl o //5-(4-(2-(5-amino-8-methylbenzo|S/1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate; 5-(4-(2-(5-amino-8-methylbenzo|SHI, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoic acid; 2-(4-(2-(5-amino-8-methylbenzo C(1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 4-(2-(5-amino-8-methylbenzo DI, 7Inaphthyridin-2-yl)ethyluphenylethyl carbonate; methyl 4-(4-(2-(5-amino-Y-methylbenzo DP, 7|Inaphthyridin-2-yl)ethyluphenoxy)butanoate; 4-(4-(2-( 5-amino-8-methyl-benzo|D/1,7|naphthyridin-2-yl)uethyl)uphenoxy)butyric acid; 4-(4-(2-(5-amino-8-methylbenzo)/1,7 |Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)butyric acid; 2-(4-(isopentyloxy)-2- methylphenethyl)-8-methylbenzo DCP, 7|Inaphthyridin-5-amine;. 4-(2- (5-amino-8-methylbenzo|D/I1,7UInaphthyridin-2-yl)/ethyl)phenylhexylcarbonate; 2-(2,4,6-trimethylphenethyl)-benzo|DI1,7|naphthyridin-5-amine; (5 -amino-2-(2,4-dimethylphenethyl)benzo DP, 7|Inaphthyridin-8-yl)methanol, diethyl 3-(2-(4-(2-(5-amino-8-methylbenzo) Х/1.7 |Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)propylphosphonate; diethyl 3-(2-(2-(4-(2- (5-amino-8-methylbenzo| DI, 7)|Inaphthyridin-2- yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)propylphosphonate; 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3-methylphenyl dim ethyl sulfamate; (5-amino-2- (4-(dimethylamino)phenethyl)benzo (1, 7|Inaphthyridin-8-yl)methanol; 2-(4-(dimethyl-amino)phenethyl)-8- methylbenzo ШІ, 7|Inaphthyridin -5-amine; 4-(2-(5-amino-8-methylbenzo|D(1,7|-naphthyridin-2-yl)ethyl)uphenol; 1-(4-(2-(5-amino-8 -methylbenzo|D/1,7|naphthyridin-2-yl)ethyl)phenyl)ethanone; 2-(4- ((dimethylamino)methyl)phenethyl)-8-methylbenzo|DI, 7|Inaphthyridin-5-amine; 2 -(4-(1- (dimethylamino)ethylphenethyl)-8-methylbenzo|DI1,7|naphthyridine-5-amine; 1-(4-(2-(5-amino-8- methylbenzoSHII1,7|Inaphthyridine-2- yl)ethyl)phenyl)ethanone oxime; 8-methyl-2-(4- ((methylamino)methyl)phenethyl)benzo C(1,7|Inaphthyridin-5-amine; (4-(2-(5-amino- 8- methylbenzoSHI1,7|Naphthyridin-2-yl)ethyl)benzylamino)ethanol; 8-methyl-2-(4-(pyrrolidin-1-ylmethyl)-phenethyl)benzo DI, 7|Naphthyridin-5-amine; 2- (3,4-dimethoxyphenethyl)-8-methyl-benzo DP, 7|Inaphthyridine-

B-amine;./ 2-(1-(4-(2-(5-amino-Y-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyluphenyl)ethylamino)ethanol; 1-(4-(2- ( 5-amino-8-methylbenzo|DY, 7|Naphthyridin-2-yl)ethyluphenyl)ethanol; 8-methyl-2-(4-(oxazol-5-ylopheneethyl)benzo|DY, 7|Naphthyridin-5-amine; 3-(1-(4-(2-(5-amino-8-methylbenzo|C1, 7U|Inaphthyridin-2-yl)ethyl)phenyl)ethylamino)propanenitrile; (22)-2-(1-(4- (2-(5-Amino-Y-methylbenzo, 7|naphthyridin-2-yl)ethylphenyl)ethylamino)propan-1-ol; 8-methyl-2-(4-(1-(piperazin-1-yl) 'ethyl)phenethyl)benzo DY, 7|naphthyridin-5-amine; ((25)-1-(1-(4-(2-(5-amino-8- methylbenzo ЦІ1,7|inaphthyridin-2-yl) ethyl)phenyl)ethyl)pyrrolidin-2-ylmethanol; dimethyl-ethane-1, 2-diamine; 3-(1-(4-(2-(5-amino-8-methylbenzo-CHI, 7|Inaphthyridin-2-yl)ethyl)phenyl)-ethylamino)propanoic acid; 8 -methyl-2-(4-(1-(4-methylpiperazin-1-yl)uethylphenethyl)-benzo|DI, 7|naphthyridin-5-amine; M2-(1-(4-(2-(5-amino) -8- methylbenzo Х/1,7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)-M1,M1-dimethylpropane-1 2-diam others; 8-methyl-2-(4-(1- (2-(pyridin-4-yl)uethylamino)ethyluphenethyl)benzo|C1, 7UInaphthyridin-5-amine; M1-(1-(4-(2-(5- amino-8- methylbenzo Х/1,7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)-M2, M2-diethylethane-1 2-diamine; 2-(4-(dimethylamino)-2-methylphenethyl)-8-methylbenzo DI, 7-Inaphthyridin-5-amine; 1-(1-(4-(2-(5-amino-8-methylbenzo)/1,7|Inaphthyridin-2-yl)ethylphenyl)ethyl)pyrrolidine-3-carboxylic acid; 4-(1-(4-(2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)phenyl)ethylamino)phenol; 1-(1-(4-(2-( 5-amino-8- methylbenzo SHІ, 7|Inaftyridin-2-yl)ethyluphenyl)ethyl)pyrrolidin-3-ol, and 2-(4-(2-aminopropan-2-ylopheneethyl)-8-methylbenzo|ЧІ1,7 |naphthyridine-5-amine.

In certain embodiments of the compounds, compositions, and compounds disclosed herein, the compound

Formula (I-A) is chosen from the following compounds and their pharmaceutically acceptable salts: 2-methylbenzo ХІ, 7|Inaphthyridin-5-amine; 2-propylbenzoic acid, 7|naphthyridine-5-amine; 2- ethylbenzo DP, 7-Naphthyridin-5-amine; 2-(3-Methoxyphenethyl)benzo CI, 7|Inaphthyridin-5-amine; 8-methylbenzol/1,7|inaphthyridin-5-amine; 8-methyl-2-phenethylbenzo| 1, 7UInaphthyridin-5-amine; methyl 5-aminobenzo| 11, 7UInaphthyridine-Z-carboxylate; (5-aminobenzoic acid, 7|naphthyridin-3-yl)umethanol; benzo DP, 7UInaphthyridin-5-amine; (5-aminobenzo|DI1,7|naphthyridin-8-yl)methanol; 2-(2-methylphenethyl)benzo|D(I1,7Inaphthyridin-5-amine; 2-(3-methylphenethyl)-benzo ZHI,7|Inaphthyridin-5-amine; 2-(4-methylphenethyl)benzo|DI1,7 |Inaphthyridin-5-amine; 8-chlorobenzo SHI, 7Inaphthyridin-5-amine; ethyl 5- aminobenzo| 11, 7UInaphthyridine-9-carboxylate; 8-methoxybenzo| 1, 7) | Inaphthyridine-5-amine; 8- (trifluoromethyl)benzo(ЦІ1,7|naphthyridin-5-amine; 8-fluorobenzo|DC11,7|naphthyridin-5-amine; 3- methylbenzo SHІ, 7|Inaphthyridin-5-amine; 3-fluorobenzo| 1, 7-Naphthyridin-5-amine; 2-phenethylbenzo|C1, 7-Naphthyridin-5-amine; 8-methyl-2-(2-(naphthalen-1-yl)uethyl/ubenzo CHY, 7|naphthyridin-5-amine; 8-methyl -2-(2-(naphthalen-2-yl)ethyl)-benzo|C1,7Naphthyridin-5-amine; 4-(2-(5-amino-8- methylbenzoS(1,7|Naphthyridin-2-yl) ethyl)-benzoic acid; 3-(2-(5-amino-8-methylbenzo(SHII1,7|Inaphthyridin-2-yl)ethyl)benzoic acid; 2-(z-chlorophenethyl)-8-methylbenzo Х/1, 7|Inaphthyridin-5-amine; 2-(2-chlorophenethyl)-8-methyl-benzo|DY, 7U|Inaphthyridin-5-amine;

(2-(5-amino-8-methylbenzoic acid, 7Inaphthyridin-2-yl)ethyl)-phenyl)methanol; 2-(4-Chlorophenethyl)-8-methylbenzoic acid, 7|Inaphthyridin-5-amine; 2-(4-butylphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-butylphenethyl)-8-methyl-benzo|C1,7|naphthyridin-5-amine; 2-(4-propylphenethyl)benzo|SHI1, 7UInaphthyridine-

B-amine; 2-(4-(trifluoromethyl)phenethyl)benzo| 1, 7|naphthyridine-5-amine; 2-(2,5-dimethylphenethyl)-8-methylbenzo Х/1,7|Inaphthyridin-5-amine;. 8-methyl-2-(4-propylphenethyl)benzo or 7|Inaphthyridin-5-amine; 8-methyl-2-(2,4,5-trimethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; 2-(2,5- dimethylphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-isopropylphenethyl)-8-methylbenzo Х/1,7|Inaphthyridin-5-amine;. 2-(4-hepgylphenethyl)-8-methylbenzo DY, 7|naphthyridin-5-amine; 2-(4-isobutoxyphenethyl)-8-methylbenzo|DC(I1,7|naphthyridin-5-amine; 2-(4-(2-methoxyethoxy)methoxy)phenethyl)-8-methylbenzo| 1, 7UInaphthyridin-5-amine; 8-methyl-2-(4-(2- phenoxyethoxy)phenethyl)benzo SHI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(4-phenylbutoxy)-phenethyl)benzo DY, 7|naphthyridin-5-amine; / 2-(4-(allyloxy)phenethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(3-phenylpropoxy)uphenethyl)benzo DP, 7|Inaphthyridin-5-amine; 2-(4-(heptan-4-yloxy)phenethyl)-8-methylbenzo DI, 7|naphthyridin-5-amine; 8-methyl-2-(4-(4-methylpent-3-enyloxy)phenethyl)benzo CI, 7-Naphthyridin-5-amine; 2-(4-(2-Cyclohexylethoxy)-phenethyl)-8- methylbenzo SHHI, 7|Inaphthyridin-5-amine; 2-(4-isopropoxyphenethyl)-8-methyl-benzo|CI1, 7|Inaphthyridin-5-amine; 2-(4-(3,3-dimethylbutoxy)phenethyl)-8-methyl-benzo|CI1, 7-Naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(4-(dimethylamino)phenethyl)-benzo[1,7]-naphthyridin-5-amine; 8-(2-Cyclopropylethyl)-2-(2,4-dimethylphenethyl)-benzo|CI1, YInaphthyridin-5-amine; IM-(4-(2-(5-amino-8- methylbenzo C1,7|Naphthyridin-2-yl)ethylphenyl)acetamide; M-(4-(2-(5-aminobenzo|DI1,7|naphthyridin-2) - yl)ethyl)phenyl)acetamide; M-(4-(2-(5-amino-8-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)phenyl)-4-methylbenzenesulfonamide; 3-methyl-9- p-tolyl-9,10-dihydrobenzoHPfuroi(2,3-811,7|naphthyridin-6-amine; 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3- methylbenzonitrile; 4-(2-(5-amino-8- methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-M-(2-aminoethyl)-3-methylbenzamide; 8-methyl-2-(2 -methyl-4-(1H-tetrazol-5-ylophenethyl)benzo DP, 7|Inaphthyridin-5-amine; methyl 2-(4-(2-(5-amino-8- methylbenzo) /1,7|Inaphthyridin -2-yl)ethyl)-3-methylbenzamido)-4-methylpentanoate; methyl 2-(4-(2-(5-amino-8-methylbenzo|DY, 7Inaphthyridin-2-yl)ethyl)-3-methylbenzamido) acetate; 2-(4-(2-(5-amino-8-methylbenzo[1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamido)-4-methylpentanoic acid; /2-(4-( 2-(5-amino-8-methylbenzo ЧИ, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamido)acetic acid; /6-(5-amino-8-methylbenzo ЦИ1,7|Inaphthyridin-2-yl) )hexane-1-o l; 7-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl-heptanoic acid; 11-(5-amino-8-methyl-benzo)/1,7-Naphthyridin-2-ylundecan-1-ol; ethyl 2-(4-(2-(5-amino-8-methyl-benzo DY, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)acetate; 2-(4-(2-(5-amino- 8-methyl-benzo DP, 7-Naphthyridin-2-yl)ethyl)-3-methylphenoxy)acetic acid; 3-(4-(2-(5-amino-8-methyl-benzo IP), 7-Naphthyridin-2-yl)ethyl )-3-methylphenoxy)propanoic acid; 6-(4-(2-(5-amino-8- methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)caproic acid; 8-methyl -2-(2-methyl-4-(methylthio)phenethyl)benzo DP, 7|Naphthyridin-5-amine; 8-methyl-2-(4-(methylsulfonyl)-phenethyl)benzo DI, 7|naphthyridine-5- amine; 2-(4-«(hexyloxy)phenethyl)-8-methyl-benzo|DI, 7|Inaphthyridine-

B-amine; 8-methyl-2-(4-phenethoxyphenethyl)benzo| DY, 7|naphthyridine-5-amine; 8-methyl-2-(4-(pentyloxy)phenethyl)benzo| DY, 7|naphthyridine-5-amine; 8-methyl-2-(4-(4-methylpentyloxy)phenethyl)benzo|C1, 7-Naphthyridin-5-amine; 2-(2-fluorophenethyl)-benzo DP, 7UInaphthyridin-5-amine; 2-(3-fluorophenethyl)benzo (DI, 7|naphthyridin-5-amine; 2-(4-fluorophenethyl)benzo|ЦІ1, YInaphthyridin-5-amine; / 2-(2-(thiophen-3-yl/ethyl) /benzo|CI1, YInaphthyridin-5-amine; (5-aminobenzosHI, 7|naphthyridin-2-yl)methanol; 2-(3,4-dimethylphenethyl)-benzo DP, 7|Inaphthyridin-5-amine; /2- (3,4-Dimethylphenethyl)-8-methylbenzo (1, 7|Inaphthyridin-5-amine; /2-(3,5-Dimethylphenethyl)-8-methylbenzo SHHI, 7|Inaphthyridin-5-amine; /2-( 2-(Benzofuran-5-yl)ethyl)-8-methylbenzo CI, 7-Inaphthyridin-5-amine; 8-methyl-2-(2-nitroethyl)-benzo DY, 7|Inaphthyridin-5-amine; 2-(aminomethyl )-8-methylbenzo|C(1,7|Inaphthyridin-5-amine; M-,8-dimethylbenzo| CP, Uinaphthyridin-2,5-diamine; 2-(5-amino-8- methylbenzo Х/1,7 |Naphthyridin-2-yl)-1-phenylethanol; 2-(5-amino-8-methylbenzo(C1,7|naphthyridin-2-yl)-1-(4-methoxyphenyl)ethanol; 2-(biphenyl-2- yl)y-Y-methylbenzo 1, 7|Naphthyridin-5-amine; 2-(2-(2,6- dimethylpyridin-3-yl/ethyl)-8-methylbenzo CI, 7|Naphthyridin-5-amine; / 2-(2-(5-methoxypyridin-2-yl)ethyl)-8-methyl-benzo|DI1,7|naphthyridin-5-amine; 3-(4-(2-(5-amino-8-methylbenzo| D/I1, 7|Inaftyr idin-2-yl)ethyl)-phenyl)propanoic acid; 5-(2-(5-amino-8-methylbenzo|(DI1,7|naphthyridin-2-yl)ethyl)-4-methylpyridin-2(1H)-one; 6-(2-(5-amino-8 -methylbenzo|DI, 7|naphthyridin-2-yl)ethyl)pyridin-3-ol; 8-methyl-2-(4-(trifluoromethoxy)phenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(2 -(2,3-dihydro-1H-inden-5-yl)ethyl)-8-methylbenzo SH, 7|Inaphthyridin-o-amine; /-2-(2-(2,3-dihydro-1H-inden- 5-yl)/'ethyl)/benzo DI, 7|Naphthyridin-5-amine; (E)-3-(4-(2-(5-amino-d-methylbenzo CHY, 7|naphthyridin-2-yl) ethyl)-3-methylphenyl)acrylic acid; (E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo TSI, 7|Inaphthyridin-8-yl)acrylate; (E)- 8-(2-cyclopropylvinyl)-2-phenethyl-benzo DI, 7|naphthyridine-5-amine; 8-pentylbenzo|D(1,7|naphthyridine-5-amine; (E)-8-(2-cyclopropylvinyl/ benzo CH, 7|Inaphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-phenethyl-benzo DP, 7UInaphthyridin-5-amine; (5-amino-2-phenethylbenzo| 1, 7UInaphthyridin-8-yl) umethanol; (5-amino-2-(4-methoxy-2-methylphenethyl)benzo|C1, 7|Inaphthyridin-8-yl)umethanol; 3-(2-(5-aminobenzo| 411, 7UInaphthyridin-2-yl) uethyl phenol; 2-(2-methoxyphenethyl)-be nzo| DY, 7|naphthyridine-5-amine;

2-(4-ethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; 2-(4-ethylphenethyl)-8-methylbenzo OR, 7|naphthyridine-

B-amine; 2-(4-(dimethylamino)-phenethyl)-benzo CH, 7|naphthyridin-5-amine; 2-(4-(piperidin-1-ylphenethyl)benzo|DI1,7|naphthyridine-5-amine; 2-(4-tert-butylphenethyl)-8-methylbenzo|

B-amine; 8-methyl-2-(4-(piperidin-1-yl/uphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-methoxyphenethyl)-8-methylbenzo HCI, 7|naphthyridin-5-amine; /2-(3,5-dimethoxyphenethyl)-8-methylbenzo|CP1, 7|Inaphthyridin-5-amine; 8-methyl-2-(2-«-trifluoromethyl)phenethyl)benzo TSI, 7|Inaphthyridin-5 -amine; 4-(2-(5-amino-8-methylbenzo ХІ, 7|Inaftyridin-2-yl)ethyl)-M-hydroxybenzimidamide; 4-(2-(5-amino-8-methylbenzol,7|inaphthyridin-2-yl)ethyl)benzonitrile; 8-methyl-2-(4-(1-morpholinoethyl)-phenethyl)benzo DY, 7|naphthyridin-5-amine;. 2-(4-aminophenethyl)-8-methylbenzo CH, 7|Inaphthyridin-5-amine; 1-(4-(2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)ethyl)phenyl)guanidine; 8-methyl-2-(4-(1- (phenethylamino)ethyl/phenethyl)benzo CI, 7|Inaphthyridin-5-amine; 2-(4-(2-(5-amino-8- methylbenzoSHII1,7|Inaphthyridin) -2-yl)ethyl)phenyl)acetonitrile; 2-(4-(piperidin-1-ylmethyl)-phenethyl)benzo, 7|naphthyridin-5-amine; 1-(4-(2-(5-aminobenzo) . phenethyl)benzo|ЦІ1, 7ІNaphthyridin-5-amine; 2-(4-(2-aminopropan-2-ylphenethyl)benzo| ДІ, 7|naphthyridin-5-amine; 1-(1-(4-(2-( 5-aminobenzo CHY, 7|Inaphthyridin-2-yl)/ethylphenyl)ethyl)pyrrolidine-3-carboxylic acid; 8-methyl-2-(4-(1-(phenylamino)ethyl)-phenethyl)benzo DHY, 7| Naphthyridin-5-amine; 2-ethyl-8-methylbenzo C1,7|Inaphthyridin-5-amine; (5-amino-8-methylbenzo H/1,7|Inaphthyridin-2-ylmethanol; 8-methyl-2-propylbenzo | SHІ, 7|Inaphthyridin-5-amine; /-2-(2-(1H-indol-5-yl)ethyl)-8-methylbenzo CI, 7|Inaphthyridin-5-amine; 2-(4- ethoxyphenethyl)-8-methylbenzo ХИ1,7|Inaphthyridin-5-amine; 8-methyl-2-(4-phenoxyphenethyl)-benzog(PCІ1,7|naphthyridin-5-amine; 2-(2, 4-dimethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; 2-(2,4-dimethylphenethyl)-8-methylbenzo Х/1,7|Inaphthyridin-5-amine;. 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo CH, 7|naphthyridine-

B-amine; 4-(2-(5-amino-1-methylbenzopyridine, 7-inaphthyridin-2-yl)ethyl)-3-methylphenol; 2-(2-(2,3- dihydrobenzofuran-5-yl)ethyl)-8-methylbenzo DP, 7|Inaphthy-ridin-5-amine; 2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethanol; 3-methyl-9-phenyl-9,10-dihydrobenzo|Pfuro|2,3-

BI, 7|Inaphthyridin-6-amine; 8-methylbenzo DI, 7|naphthyridine-2,5-diamine; 1-(5-amino-8-methylbenzo-1,7-inaphthyridin-2-yl)upropan-2-ol; 2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)acetonitrile; M-(5-amino-d8-methylbenzo|11,7|naphthyridin-2-yl)acetamide; 2-(5-amino-8-methylbenzoic acid, 7|naphthyridin-2-yl)-1-(2,4-dimethylphenyl)ethanol; 2-(2-(6-methoxy-4-methylpyridin-3-yl)ethyl)-8-methylbenzo| DY, 7-Inaphthyridin-5-amine; 4-(4-(2-(5-amino-β8-methylbenzo DP, 7|Inaphthyridin-2-yl)/ethyl)phenyl)butan-1-ol; methyl 3-(4-(2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)/ethyluphenyl)upropanoate; 3-(4-(2-(5-amino-d-methyl- benzo DI, 7|naphthyridin-2-yl)ethylphenyl)propan-1-ol; 4-(4-(2-(5-amino-8-methyl-benzo DP, 7|naphthyridin-2-yl)ethyl)phenyl )-2-methylbutan-2-ol; 2-(4-(aminomethyl)phenethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine; (E)-ethyl 3-(4-(2-(5- amino-8-methyl-benzo DP, 7-Naphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate; ethyl 3-(4-(2-(5-amino-8-methyl-benzo) IP, 7-Naphthyridin-2-yl) )ethyl)-3-methylphenyl)propanoate; 2-(4-(2-(5-amino-8-methyl-benzo DP, 7UInaphthyridin-2-yl)ethyl)-3-methylbenzyl)propane-1,3-diol 3-(4-(2-(5-amino-8-methylbenzo)/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenylpropanoic acid; 5-amino-2-(4-methoxy-2- methylphenethyl)benzo|D(I1,7Inaphthyridin-8-carbaldehyde; ethyl 4-(2-(5-amino-8- methylbenzoSHII1,7|Inaphthyridin-2-yl)ethyl)benzoate; 8-methyl-2-(4- methylphenethyl)-benzo DP, 7UInaphthyridin-5-amine; 2-(4-(2-(5-amino-8-methylbenzo| DI, 7|naphthyridin-2-yl)ethyluphenyl)upropan-2-ol; / (4 -(2-(5-amino-8-methylbenzo| 1, 7-Naphthyridin-2-yl)ethyl)phenyl)-methanol; ethyl 4-(2-(5-amino-8-methylbenzo CI, 7-Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 4-(2-(5-amino-8-methylbenzo H1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoic acid; (4-(2-(5-amino-8-methylbenzo 1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)methanol; 8-methyl-2-(2,4,6- trimethylphenethyl) benzo CHY, 7|Inaphthyridin-5-amine; /2-(4-(2-(5-amino-8H-methylbenzo CI, 7-Naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol; 8-methyl-2-(4-propoxyphenethyl)benzo DY, 7|naphthyridin-5-amine; (E)-3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo DP, 7|Inaphtyridin-8-yl)acrylic acid; ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|ЦИ1, YInaphthyridin-8-ylpropanoate; 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|DI . -8-ol; /-5-aminobenzo|CI, 7UInaphthyridine-8-carbaldehyde; 1-(5-aminobenzo ZHI, 7|Inaphthyridin-8-yl)ethanol; - 1-(5-aminobenzo|CI, 7UInaphthyridin-8 -yl)ethanone; 8-isopropyl-benzo CH, 7|Inaphthyridin-5-amine; 8-vinylbenzo DP, 7Inaphthyridin-5-amine; 8-ethyl-benzo DP, 7|Inaphthyridin-5-amine; 8-(Methoxymethyl )benzo|D/I1, 7Inaphthyridin-5-amine; (5-amino-2-(4- methoxyphenethyl)benzo ХІ, 7Inaphthyridin-8-yl)methanol; benzoІІ, "I naphthyridine-5,8-diamine; 8- (aminomethyl)benzo C(1,7|Inaphthyridin-5-amine; 3-fluoro-8-methyl-benzo DI, 7|naphthyridin-5-amine; (5-amino-

3-fluorobenzoic acid, 7-naphthyridin-8-yl)methanol; Z-chlorobenzo SHI, 7-Naphthyridine-5,8-diamine; 3-fluorobenzoic acid, 7|Inaphthyridine-5,8-diamine; 8-isobutylbenzo|DY1,7|naphthyridine-5-amine; (E)-8-(prop-1-enyl)benzo SH, 7|naphthyridin-5-amine; 8-propylbenzo, 7|Inaphthyridin-5-amine; 8-(2-cyclopropylethyl)benzo|(ЦІ1, Naphthyridin-5-amine; 8-phenethylbenzo DI, 7|naphthyridin-5-amine; (5-amino-

2-(4-bromophenethyl)-benzo[1,7]naphthyridin-8-yl)methanol; 2-(4-methoxy-2-methylphenethyl)-8-pentyl-benzo DP, 7-Naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(4-methoxy-2-methylphenethyl)-benzo DP, 7UInaphthyridin-5-amine; (5-amino-2-(2,4,6-trimethylphenethyl)benzo CHY, 7|naphthyridin-8-ylmethanol; (5-amino-2-(4-propoxyphenethyl)benzo C1,7|naphthyridin-8-yl) umethanol; (2-(2-(1H-indol-5-yl)ethyl)-o-aminobenzo| DP, 7|Inaphthyridin-8-yl)methanol; methyl 4-(2-(5-amino-8- methylbenzo SH, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 4-(2-(5-amino-8- methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-M, 3-dimethylbenzamide ; M-(2-acetamidoethyl)-4-(2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamide; 4-(2-(5-amino-8 - methylbenzo SHI, 7|Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide; 2-(4-methoxyphenethyl)benzo SHHI, 7Inaphthyridin-5-amine; 2- (4-methoxy-2-methylphenethyl)-benzo DP, 7-Naphthyridin-5-amine; 4-(2-(5-amino-8-methylbenzo (1,7 |naphthyridin-2-yl)ethyl)-3-methylbenzamide; 4-(2-(5-amino-Z-methylbenzo 1, 7|Inaphtyridin-2-yl)ethyl)-M, M,Z-trimethylbenzamide; 4-(2-(5-amino-8-methylbenzo| DP, 7|Naphthyridin-2-yl)ethyl)-M-(2-hydroxy-ethyl)-3-methylbenzamide; 4-(2-(5-amino-8-methylbenzo CHY, 7|naphthyridin-2-yl)ethyl) -M-(2-(dimethy lamino)ethyl)-3-methylbenzamide; (4-(2-(5-amino-8-methylbenzo ЧИ, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)(pyrrolidin-1-yl)methanone; 4-(2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)-N-(2-(diethylamino)ethyl)-3-methylbenzamide; (4-(2-(5-amino-8- methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazine-1-ylumethanone; (4-(2-(5 -amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)(piperazin-1-yl)methanone; 4-(2-(5-amino-8-methylbenzo CI1,7| Inaphthyridin-2-yl)ethyl)-3-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamide; 4-(2-(5-aminobenzo|CI, 7UInaphthyridin-2-yl)ethyl)- M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide; /-4-(2-(5-amino-8-methyl-benzo DY, 7|naphthyridin-2-yl)ethyl)-M-( 2-(dimethylamino)ethyl)-N-methylbenzamide; 2-(4-(2-(5-aminobenzo|(DI,7|naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol; 2 -(4-butoxyphenethyl)-8- methylbenzo SHI, 7|Naphthyridin-5-amine; 2-(2-(biphenyl-4-yl)ethyl)-8-methylbenzo DI, 7|Naphthyridin-5-amine; 2- (1,3-Dihydroisobenzofuran-1-ylylmethyl)-8-methylbenzo CY, 7-Inaphthyridin-5-amine; 8-methyl-2-(4-(2- methylallyloxy)phenethyl)-benzogPSHI1, 7|Inaphthyridin-5-amine; 2-(4-(Isopentyloxy)phenethyl)-8-methylbenzo CI, 7|Inaphthyridin-5-amine; 4-(2-(5-amino-8-methylbenzo DP, 7|Inaphthyridin-2-yl)/ 'ethyl phenylpropyl carbonate; ethyl 5-(4-(2-(5-amino-8-methylbenzo CI, 7Inaphthyridin-2-yl)/ethylphenoxy)pentanoate; 2-(4-(cyclopentyloxy)phenethyl)-8-methylbenzo|DC(І1,7 |Naphthyridin-5-amine; 2-(4-(cyclobutylmethoxy)phenethyl)-8-methylbenzo| 1,7-Naphthyridin-5-amine; 8-methyl-2-(4-(2-morpholinoethoxy)phenethyl)benzo| DI, 7|Inaphthyridin-5-amine; 2-(4-(2-(5-amino-8- methylbenzo 1,7|Inaphthyridin-2-yl)ethyluphenoxy)-1-phenylethanone; 5-(4-(2-( 5-amino-8-methylbenzo ЦІ1,7|Inaphthyridin-2-yl)uethylphenoxy)pentanoic acid; 2-(4-(2-(5-amino-8-methylbenzo ХІ1,7|Inaphthyridin-2-yl)uethylphenoxy) ethanol; 2-(4-(2-(5-amino-8- methylbenzo Х/1,7|Inaphthyridin-2-ylluethylufenoxy)-M, M-dimethylacetamide; 8-methyl-2-(2-methyl-4- (2-morpholinoethoxy)phenethyl)benzo|DY,7|Inaphthyridin-5-amine; 2-(2-(4-(2-(5-amino-8-methylbenzo)/1,7|Inaphthyridin-2-yl) ethyl)-3-methylphenoxy)ethoxy)ethanol; diethyl 3-(4-(2-(5-amino-8- methylbenzo TSI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate; 3-( 4-(2-(5-amino-8-methylbenzol/1,7|inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate acid; 2-(4-butoxy-2-methylphenethyl)-8-methylbenzo DCP, 7-Naphthyridin-5-amine; 2-(4-(2-(5-aminobenzo|DI1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 2-(2-(4-(2-(5-aminobenzo|DI1,7Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethanol; ethyl o //5-(4-(2-(5-amino-8-methylbenzo|S/1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate; 5-(4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoic acid; 2-(4-(2-(5- amino-8-methylbenzo C(1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 4-(2-(5-amino-8-methylbenzo DI, 7Inaphthyridin-2-yl)ethyluphenylethyl carbonate; methyl 4-(4-(2-(5-amino-8-methylbenzo DP, 7|Inaphtyridin-2-yl)ethylufenoxy)butanoate; 4-(4-(2-(5-amino-8-methylbenzo C1,7| Inaphthyridin-2-yl)uethylphenoxy)butyric acid; 4-(4-(2-(5-amino-8-methylbenzo)/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)butyric acid; 2 -(4-(Isopentyloxy)-2-methylphenethyl)-8-methylbenzo DCP, 7|Inaphthyridin-5-amine; 4-(2-(5-amino-8-methylbenzo|D/I1, 7UInaphthyridin-2-yl) )/ethyl)phenylhexylcarbonate; 2-(2,4,6-trimethylphenethyl)-benzo|DI1,7|naphthyridine-5-amine; (5-amino-2-(2,4-dimethylphenethyl)benzo DP, 7|Inaphthyridine -8-yl)methanol, diethyl 3-(2-(4-(2-(5-amino-8-methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)propylphosphonate; diethyl 3-(2-(2-(4-(2- (5-amino-8-methylbenzo|DI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)eth xy)propylphosphonate;

4-(2-(5-amino-8-methylbenzo DP, 7-Inaphthyridin-2-yl)ethyl)-3-methylphenyldimethylsulfamate; (5-amino-2- (4-(dimethylamino)phenethyl)benzo (1, 7|Inaphthyridin-8-yl)methanol; 2-(4-(dimethylamino)phenethyl)-8- methylbenzo SH, 7|Inaphthyridin-5 -amine; /4-(2-(5-amino-1-methylbenzo H(1,7|Inaphthyridin-2-yl)ethyl)uphenol; 1-(4-(2-(5-amino-8-methylbenzo| D/1,7|Naphthyridin-2-yl)ethyl)phenyl)ethanone; 2-(4- ((dimethylamino)methyl)phenethyl)-8-methylbenzo| 1,7UInaphthyridin-5-amine; 2-(4-( 1-(Dimethylamino)ethylphenethyl)-8-methylbenzo|DI1,7|naphthyridin-5-amine; 1-(4-(2-(5-amino-8- methylbenzoSHIII1,7|Inaphthyridin-2-yl)ethyl)phenyl )ethanone oxime; 8-methyl-2-(4- ((methylamino)methyl)phenethyl)-benzoХ/1,7Inaphthyridin-5-amine; (4-(2-(5-amino-8- methylbenzoХІ1,7|Inaphthyridine -2-yl)ethyl)benzylamino)ethanol; 8-methyl-2-(4-(pyrrolidin-1-ylmethyl)phenethyl)-benzo SHI, 7|Inaphthyridin-5-amine; 2-(3,4-dimethoxyphenethyl) -8-

methylbenzo SH, 7|Inaphthyridin-5-amine; 2-(1-(4-(2-(5-amino-8-methylbenzoyl, 7-inaphthyridin-2-yl)ethyl)uphenyl)ethylamino)ethanol; 1-(4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)/ethyluphenyl)ethanol; 8-methyl-2-(4-(oxazol-5-ylophenethyl)benzo DP, 7| naphthyridin-5-amine; 3-(1-(4-(2- (5-amino-8-methyl-benzo|DI1,7|naphthyridin-2-yl/ethyl)phenyl)ethylamino)propanenitrile; (2K)- 2-(1-(4-(2-(5-amino-8-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl)phenyl)ethylamino)propan-1-ol; 8-methyl-2-(4- (1- (piperazin-1-yl)oethylufenethyl)benzo DP, 7|Inaphthyridin-5-amine; ((25)-1-(1-(4-(2-(5-amino-8- methylbenzo ЦИ1,7) |Inaphthyridin-2-yl)ethyluphenyl)ethyl)pyrrolidin-2-ylmethanol; )ethyl)-M2,M2-dimethylethane-1 2-diamine; 3-(1-(4-(2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyluphenyl)ethylamino)upropano acid; 8-methyl-2-(4-(1-(4- methylpiperazin-1-yl)uethylufenethyl)benzo DP, 7|Inaphthyridin-5-amine; M2-(1-(4-(2-(5- amino-8-methylbenzo|C(1,7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)-M',M'-dimethylpropane-1 2-diamine; 8-methyl-2-(4-(1- (2 -(pyridin-4-yl)ethylamino)ethyl)-phenethyl)-benzoyl 7|naphthyridin-5-amine; M1- (1-(4-(2-(5-amino-8-methylbenzo|C1,7|Inaphthyridin-2-yl)ethyl)phenyl)ethyl)-Me, Me-diethylethane-1 2-diamine;. 2-(4-(Dimethylamino)-2-methylphenethyl)-8-methylbenzo DI, 7-Naphthyridin-5-amine; 1-(1-(4-(2-(5-amino-8- methylbenzo Х/1,7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)pyrrolidine-3-carboxylic acid; 4-(1-(4- (2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)phenyl)ethylamino)phenol; 1-(1-(4-(2-(5-amino-8-methylbenzo) SHI) .

In certain embodiments of the compounds of Formula (XMI), or a pharmaceutically acceptable salt thereof, each

VU, VA and KZ are independently chosen from the following:

Бе -СНг8ОоСНзи, -СООСНоСН:И, СНгОСНаСН», -М(СН3)г, -(О(СНг)г)22 ОН, -О(СНг)»2А-ОН, -О(СНег)г-а- ( РозН2г), -"Ф(СНг)»2:4-СООН, -О(СНг)24-СН(СНЗ3)2, С2-Свё alkyl substituted with 1-3 substituents selected from such as: -ОН , -CH3, cyclopropyl, -O(CHg)24-COOH, -O(CHg)24(POzH»g). - UNO,

СООСН», and -СООСНеСН:». In other embodiments of the compounds of the Formula (XMI), K" is H. In other embodiments, such compounds of the Formula (XM) have from one to three KZ groups. In other embodiments of such compounds of the Formula (XMI), 2" is H or Me. In other embodiments, the following compounds of Formula (XMI) have two VZ groups selected from the group including: -СН3, -СНеСН3в, -

СЕз, -СН2ОН, -ОСН», -СООСН», -СООСНеСН;,, E, SI, Vi, -СНg8ОсСН», СНgОСНесСнН», -M(СН3)»r, -(О(СН?r)r)» -

AOH, -O(CHg)2-OH, -O(CH2g)2-4-(POzHg), -O(CHg)24-COOH, -O(CHg)24-CH(CHNZ)", C2-Cv alkyl , substituted with 1-3 substituents selected from: -OH, -CH3, cyclopropyl, -O(CHg)»2-4-COOH, -

О(CHg)24А(РозНег), -СООН, СООСН», and -СООСНеСН:». In other embodiments, the following compounds of the Formula (XMI) are selected from such as /2-(4-(2-(5-amino-d-methylbenzo|DY, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)propane -2-ol; / 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo SHHI, 7-Naphthyridin-5-amine; -2-(2,4-dimethylphenethyl)-benzo|C(1,7UInaphthyridin-5-amine; ethyl 4-(2-(5-amino-8- methylbenzo ХІ, 7|Inaphthyridin-2-yl)ethyl)- 3-Methylbenzoate, 2-(4-Dimethylamino)phenethyl)-8-methylbenzol, 7|Inaphthyridin-5-amine, and 2-(4-Methoxyphenethyl)-8-methylbenzol/1,7Inaphthyridin-5-amine.

In another aspect, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) described above and a pharmaceutically acceptable carrier.

In certain embodiments of this aspect, the pharmaceutical composition is formulated for intravenous administration, intravenous administration, intramuscular administration, oral administration, rectal administration, administration by inhalation, nasal administration, topical application, ophthalmic administration, or auricular administration. In other embodiments, the pharmaceutical compositions are in the form of a tablet, pill, capsule, liquid, inhalation solution, nasal spray solution, suppository, solution, emulsion, ointment, eye drops, or ear drops. In other embodiments, such pharmaceutical compositions additionally include one or more additional therapeutic agents.

In another aspect, the present disclosure provides medicaments for the treatment of a disease or disorder in a patient involving modulation of a TIC receptor, and such medicaments comprise a therapeutically effective amount of a compound of Formula (I). In certain embodiments of such drugs, the TIC receptor is TIC K7. In other embodiments of such drugs, the TI E receptor is TI K8. In certain embodiments of such drugs, the compound is a TIC receptor agonist. In certain embodiments of such drugs, the compound is an agonist of the TI K7 receptor. In certain embodiments of such drugs, the compound is an agonist of the TI K8 receptor.

In another aspect, the present disclosure provides the use of a compound of Formula (I) in the manufacture of a medicament for the treatment of a disease or disorder in a patient involving modulation of a TIC receptor.

In another aspect, the present disclosure provides methods of modulating a TIC receptor, wherein said methods comprise administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, thereby modulating TIC receptor. In certain embodiments of such methods, the TIC receptor is a TIC K7. In other embodiments of such methods, the TI Kk receptor is a TI K8. In certain embodiments of such methods, the compound is an agonist

TIC of the receptor. In certain embodiments of such methods, the compound is an agonist of the TI K7 receptor. In certain embodiments of such methods, the compound is an agonist of the TI K8 receptor.

In certain embodiments of such methods, the methods include administering the compound to a cellular or tissue system or to a human or animal.

In certain embodiments, these methods are provided herein for treating a subject for a specific condition or disorder involving a TIC, such methods further comprising the optional step of identifying a subject in need of such treatment.

Another aspect provided herein includes methods of treating a disease or disorder involving modulation of a TC receptor, wherein said method comprises administering to a system or subject in need of such treatment an effective amount of a compound of Formula (I), or thereof pharmaceutically acceptable salts or pharmaceutical compositions, thereby treating the disease or disorder. In certain embodiments of such methods, the TC receptor is TI K7. In other embodiments of such methods, the TIC receptor is TI K8. In certain embodiments of such methods, the compound is an agonist of the TIC receptor. In certain embodiments of such methods, the compound is an agonist of the TI K7 receptor. In certain embodiments of such methods, the compound is an agonist of the TI K8 receptor. In certain embodiments of such methods, the methods include administering the compound to a cellular or tissue system or to a human or animal.

In certain embodiments of such methods, the disease or pathological condition is an infectious disease, an inflammatory disease, a respiratory disease, a dermatological disease, or an autoimmune disease. In certain embodiments of such methods, the disease or pathological condition is asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ADS5), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, senile keratosis, basal cell epithelioma, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, breast cancer, NIM or lupus.

Another aspect provided herein includes methods of treating a cell proliferative disease comprising administering to a system or subject in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof; wherein the cell-proliferative disease is lymphoma, osteosarcoma, melanoma, or a tumor of the breast, kidney, prostate, colorectal, thyroid, ovary, pancreas, nerve cells, lung, uterus, or gastrointestinal tract.

In another aspect, the present disclosure provides a pharmaceutical composition that includes a compound

Formulas (I) (I-A), an antigen and a pharmaceutically acceptable carrier, wherein said pharmaceutical compositions are immunogenic compositions, and the compound is an immune potentiator, and is present in an amount effective to enhance an immune response to the antigen in a subject, which receives the composition. In certain embodiments, such pharmaceutical compositions additionally include one or more immunoregulatory agents. In certain embodiments, one or more immunoregulatory agents include one or more adjuvants. In certain embodiments, such adjuvants are selected from adjuvants such as: a composition containing mineral substances, an oil emulsion, a saponin composition, a virus-liposome vaccine, a virus-like particle, a bacterial derivative, a microbial derivative, a human immunomodulator, a bioadhesive substance, mucoadhesive substance, microparticle, liposome, polyoxyethylene ester composition, polyoxyethylene ester composition, polyphosphazene, muramyl peptide, or imidazoquinolone compound. In certain embodiments, the adjuvant is an oil emulsion. In certain embodiments, the immunogenic compositions are useful as vaccines, and the compound is present in an amount sufficient to produce an immunostimulatory effect upon administration.

Another aspect provided herein includes methods of enhancing the effectiveness of an immunogenic composition comprising adding an effective amount of a compound of Formula (I) or (I-A) to the immunogenic composition.

In another aspect, immunogenic compositions comprising a compound are provided herein

Formulas (I-A), and an antigen, wherein the amount of the compound is an amount effective to enhance an immune response to the antigen in a subject to whom the composition is administered. In certain embodiments of such immunogenic compositions, the antigen is a bacterial antigen. In certain variants of the implementation of such immunogenic compositions, the bacterial antigen is an antigen of the Meyissegia tepipodiides strain. In other embodiments of such immunogenic compositions, the antigen is a viral antigen or a fungal antigen. In other embodiments, such immunogenic compositions additionally include an additional adjuvant. In certain embodiments of such immunogenic compositions, the antigen is a polypeptide. In certain embodiments of such immunogenic compositions, the polypeptide has at least 85-95 identity to a sequence selected from the group consisting of 5ZEO IU

MoMo: 1-6 presented in this description.

BRIEF DESCRIPTION OF DRAWINGS

In fig. 1 shows the serum antibody titer with bactericidal properties ("BA") of certain compounds disclosed herein to enhance the immune response to a bacterial antigen. The compound dose in µg is shown on the left and the fold change relative to the response induced by ME59/3MepvB is shown on the right of each bar. The results are equated to "Cro" (Cro oligonucleotide), K848, and

Ittidshitoa (Itib).

In fig. 2 shows the titer of the serum antibody with bactericidal properties ("BA") of compound 47, disclosed herein, for enhancing the immune response to a bacterial antigen. Compound dose in μg is shown on the left, and fold change relative to the response induced by ME59/3MepB is shown to the right of each bar. Results were compared to "Cr" (CrO oligonucleotide), K848, and Ittidcytoa (Itib)).

In fig. C shows the titer of serum antibody with bactericidal properties ("BA") of compound 47, disclosed herein, to enhance the immune response to a bacterial antigen. Compound dose in μg is shown on the left, and fold change relative to the response induced by ME59/3MepB is shown to the right of each bar. The results were compared to "Sre" (Sro oligonucleotide), K848, and Ittidcytoy (Itib)).

In fig. 4 shows the titer of a serum antibody with bactericidal properties ("BA") of compound 169 disclosed herein for enhancing the immune response to a bacterial antigen. Compound dose in μg is shown on the left, and fold change relative to the response induced by ME59/3MepB is shown to the right of each bar. The results were compared to "Sre" (Sro oligonucleotide), K848, and Ittidcytoy (Itib)).

In fig. 5 presents a summary of the data shown in Figures 1-4.

DETAILED DESCRIPTION OF THIS INVENTION

Definition

The term "alkenyl" as used herein refers to a partially unsaturated branched or straight chain hydrocarbon having at least one carbon-carbon double bond. Atoms located around the double bond are either in cis (7) or trans (E) conformation. The alkenyl group may be optionally substituted. As used herein, the terms "Co-Salkenyl", "Co-Slalkenyl", "Co-Svalkenyl", "Co-Svalkenyl", "Co-C7alkenyl", and "Co-

Alkenyl" refers to an alkenyl group containing at least 2, and no more than 3, 4, 5,6, 7, or 8 carbon atoms, respectively. Unless otherwise specified, an alkenyl group is generally

C2-Cv alkenyl. Non-limiting examples of alkenyl groups as used herein include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like.

The term "alkenylene" as used herein refers to a partially unsaturated branched or straight-chain divalent hydrocarbon radical derived from an alkenyl group. The alkenylene group may be optionally substituted. As used herein, the terms "Co-Szalkenylene", "Co-Slalkenylene", "Co-Swalkenylene", "Co-Swalkenylene", "Co-

C7alkenylene" and "Co-Swalkenylene" refer to an alkenylene group containing at least 2, and no more than 3, 4, 5, 6, 7, or 8 carbon atoms, respectively. Unless otherwise specified, an alkenylene group is basically C1-C6 alkenylene Non-limiting examples of alkenylene groups as used herein include ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenylene, and the like.

The term "alkyl" as used herein refers to a saturated branched or straight chain hydrocarbon. The alkyl group may be optionally substituted. As used herein, the terms "Ci-Salkyl", "Ci-Csalkyl", "Ci-Svalkyl", "Ci-Salkyl", "Ci-Stalkyl" and "Ci-Salkyl" refer to an alkyl group containing at least 1, and no more than 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. Unless otherwise indicated, the alkyl group is primarily C1-C8 alkyl.

Non-limiting examples of alkyl groups as used herein include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decile and the like.

The term "alkylene" as used herein refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkyl group.

The alkylene group may be optionally substituted. As used herein, the terms "Si-

Szalkylene", "Ci-Slalkylene", "Ci-Svalkylene", "C-Svalkylene", "Ci--Stalkylene" and "C/-Svalkylene" refer to an alkylene group containing at least 1 and no more than 3 , 4, 5, 6, 7, or 8 carbon atoms, respectively.Unless otherwise specified, an alkylene group is generally a C.1-C alkylene.

Non-limiting examples of alkylene groups, as used herein, include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, hexylene, and the like.

The term "alkynyl" as used herein refers to a partially unsaturated branched or linear hydrocarbon having at least one carbon-carbon triple bond. The alkynyl group may be optionally substituted. As used herein, the terms "C2-Salkynyl", "Co-Salalkynyl", "Co-Svalkynyl", "Co-Svalkynyl", "Co-Stalkynyl", and "Co-

Alkynyl" refers to an alkynyl group containing at least 2, and no more than 3, 4, 5,6, 7, or 8 carbon atoms, respectively. Unless otherwise specified, an alkynyl group is generally

C2-Cv alkynyl. Non-limiting examples of alkynyl groups as used herein include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like.

The term "alkynylene" as used herein refers to a partially unsaturated branched or straight-chain divalent hydrocarbon radical derived from an alkynyl group. Alkynylene group can be optionally substituted. As used herein, the terms "C2-Salkynylene", "Co-Salkynylene", "Co-Szalkynylene", "Co-Svalkynylene", "Co-C7alkynylene", and "C2o-Svalkynylene" refer to an alkynylene group that contains at least 2, and no more than 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. Unless otherwise specified, the alkynylene group is primarily a C2-Sw alkynylene. Non-limiting examples of alkynylene groups, as used herein, include ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene, nonynylene, decinylene, and the like.

The term "Alkoxy" as used herein refers to the group -OA, where Ka is an alkyl group as defined herein. Alkoxy group can be optionally substituted. As used herein, the terms "Ci-Csalkoxy", "Ci-Slalkoxy", "Ci-Csalkoxy", "Ci-Svalkoxy", "C1-

"Stalkoxy" and "Ci-Stalkoxy" group refers to an alkoxy group in which the alkyl moiety contains at least 1, and no more than 3, 4, 5, 6, 7, or 8, carbon atoms. Non-limiting examples of alkoxy groups, as used in of this description, include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butyloxy group, tert-butyloxy group, pentyloxy group, hexyloxy group, heptyloxy group, octyloxy group, nonyloxy group, decyloxy group and the like.

The term "aryl" as used herein refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in said system is aromatic, and wherein each ring in said system contains 3-7 ring members. The aryl group may be optionally substituted. Non-limiting examples of aryl groups as used herein include phenyl, naphthyl, fluorenyl, indenyl, azulenyl, anthracenyl, and the like.

The term "arylene", as used, means a divalent radical derived from an aryl group.

The arylene group may be optionally substituted.

The term "cyano" as used herein refers to the -CM group.

The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring unit. As used herein, the terms "C3-C5 cycloalkyl", "C3-C6 cycloalkyl", "C3-C7 cycloalkyl", "C3-C6 cycloalkyl", "C3-C6 cycloalkyl" and "C3-C10 cycloalkyl" refer to the cycloalkyl group, wherein the saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring unit contains at least 3, and not more than 5, 6, 7, 8, 9, or 10, carbon atoms. The cycloalkyl group may be optionally substituted. Non-limiting examples of cycloalkyl groups as used herein include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, decahydronaphthalenyl, 2,3,4,5,6,7-hexahydro-1H-indenyl and the like.

The term "halogen" as used herein refers to fluorine (P), chlorine (CI), bromine (Hg), or iodine (I).

The term "halo" as used herein refers to halogen radicals: fluorine (-E), chlorine (-Cl), bromine (-Bg), and iodine (-1).

The terms "haloalkyl" or "halo-substituted alkyl" as used herein refers to an alkyl group as defined herein substituted by one or more halogen groups, wherein the halogen groups are the same or different. The haloalkyl group may be optionally substituted. Non-limiting examples of such branched or straight chain haloalkyl groups, as used herein, include methyl, ethyl, propyl, isopropyl, isobutyl, and n-butyl, which are substituted with one or more halogen groups, wherein the halogen groups are the same or different. , including, but not limited to, trifluoromethyl, pentafluoroethyl, and the like.

The terms "haloalkenyl" or "halo-substituted alkenyl" as used herein refers to an alkenyl group as defined herein substituted by one or more halogen groups, wherein the halogen groups are the same or different. The haloalkenyl group may be optionally substituted. Non-limiting examples of such branched or straight chain haloalkenyl groups as used herein include ethenyl, propenyl, butenyl, pentenyl,

hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like, which are substituted by one or more halogen groups, wherein the halogen groups are the same or different.

The terms "haloalkynyl" or "halo-substituted alkynyl" as used herein refers to an alkynyl group, as defined above, substituted with one or more halogen groups, wherein the halogen groups are the same or different. The haloalkynyl group may be optionally substituted. Non-limiting examples of such branched or straight chain haloalkynyl groups as used herein include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, noninyl, decynyl, and the like substituted with one or more halogen groups, wherein halogen groups are the same or different.

The term "haloalkyl" as used herein refers to an alkoxy group, as defined herein, substituted with one or more halogen groups, wherein the halogen groups are the same or different. The haloalkyl group may be optionally substituted.

Non-limiting examples of such branched or straight chain haloalkynyl groups as used herein include methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, tert-butyloxy, pentyloxy, hexyloxy, heptyloxy , octyloxy group, nonyloxy group, decyloxy group and the like, substituted with one or more halogen groups, wherein the halogen groups are the same or different.

The term "heteroalkyl" as used herein refers to an alkyl group, as defined herein, in which one or more carbon atoms are independently substituted with one or more of oxygen, sulfur, nitrogen, or combinations thereof.

The term "heteroaryl" as used herein refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and wherein each ring in this system contains 3-7 ring members. A heteroaryl group may contain one or more substituents.

The heteroaryl group may be optionally substituted. Non-limiting examples of heteroaryl groups as used herein include benzofuranyl, benzofurazanyl, benzoxazolyl, benzopyranyl, benzthiazolyl, benzothienyl, benzazepinyl, benzimidazolyl, benzothiopyranyl, benzo|1,3|dioxole, benzo|bBifuryl, benzo|b|hienyl, cinnolinyl, furazanil, furyl, furopyridinyl, imidazolyl, indolyl, indolizinyl, indolin-2-one, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, 1,8-naphthyridinyl, oxazolyl, oxaindolyl, oxadiazolyl, pyrazolyl, pyrrolyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, 4H-quinolizinyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, and tetrazolyl.

The term "heterocycloalkyl" as used herein refers to cycloalkyl as defined herein wherein one or more ring carbon atoms are replaced by a residue selected from: -O-, -M-, -MV-, -F(0)-, -5-, -2(0) - or -5(0)2-, where K is hydrogen, C1-

Szalkyl or a nitrogen-protecting group, provided that the ring of the specified group does not contain two adjacent O or 5 atoms. The heterocycloalkyl group may be optionally substituted. Non-limiting examples of heterocycloalkyl groups as used herein include morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiroI(4.5|dec-8-yl, 2H- pyrrolyl, 2-pyrrolinyl, Z-pyrrolinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,4-dioxanyl, 1,4-dithianyl, thiomorpholinyl, azepanil, hexahydro-1,4- diazepinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, thioxanil, azetidinyl, oxetanyl, thietanyl, oxepanyl, thiepanyl, 1,2,3,6- tetrahydropyridinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, imidazolinyl, imidazolidinyl, 3-azabicycloI3.1.O)hexanyl, and 3-azabicycloI|4.1.O|heptanil.

The term "heteroatom" as used herein refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.

The term "hydroxyl" as used herein refers to the group -OH.

The term "hydroxyalkyl" as used herein refers to an alkyl group, as defined herein, substituted with one or more hydroxyl groups. Non-limiting examples of branched or straight-chain C 1 -C 6 hydroxyalkyl groups, as used herein, include methyl, ethyl, propyl, isopropyl, isobutyl, and n-butyl groups substituted with one or more hydroxyl groups.

The term "isocyanato" as used herein refers to the -M-C-O group.

The term "isothiocyanato" as used herein refers to the -M-C-5 group.

The term "mercaptyl" as used herein refers to the (alkyl)5- group.

The term "optionally substituted" as used herein means that said group may or may not be substituted with one or more additional group(s) individually and independently selected from alkyl, alkenyl, alkynyl , cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy group, mercaptyl, cyano group, halo group, carbonyl,

thiocarbonyl, isocyanato group, thiocyanato group, isothiocyanato group, nitro group, perhaloalkyl, perfluoroalkyl, and amino group, including mono- and di-substituted amino groups, and protected derivatives thereof.

Non-limiting examples of optional substituents include the following: halo, -CM, -O, -M-OH, -M-OB, -M-B8, -OB, -F(O)B, -C(O)OB, -ОС(О)В, -ОС(О)ОЙУВ, -С(О)МНА, -С(О)МНА», -ОС(ОМНА, -ОС(О)МН», -58-, -

З(О)В, -5(0)28, -МНА, -М(В)2, -МНОС(О)В, -"МАС(О)В, -"МНО(О)ЯВ, -МАС(ОЯВ) , 5(О)2МНВ, -5Х002М(В)", -

МНе(О)2гМА», -«МА 5(О)2МА», -МНО(О)28, -«МА5(О2В, C-Salkyl, C-Salkyloxy group, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo-substituted C:i-Salkyl, and halo-substituted C-Salkyl, where each K is independently selected from: H, halo, C-Salkyl, C-Salkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo-substituted Si -Svalkil, and halo-substituted C:i-Svalcoxy group.

The location and number of such substituent groups is consistent with the well-understood limitations of the valency of each group, for example, xO is a suitable substituent for an alkyl group but not for an aryl group.

The term "solvate" as used herein refers to a complex of varying stoichiometry formed by a solute (eg, a compound of Formula (I), or a salt thereof, as disclosed herein) and a solvent. Non-limiting examples of the solvent include water, acetone, methanol, ethanol, and acetic acid.

The term "acceptable" in relation to a formulation, composition or ingredient, as used herein, means one that does not have a long-term adverse effect on the general health of the subject being treated.

The term "administering" or "administering" a subject compound means providing the compound

Formula (I), its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or prodrug, to a subject in need of such treatment.

The term "cancer" as used herein refers to the abnormal growth of cells that is directed to proliferation in an uncontrolled manner and, in some cases, to metastasis (spreading). Cancer types include, but are not limited to, solid tumors (such as solid tumors of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organ (thyroid gland), prostate, skin (melanoma), or blood tumors (such as leukemia).

The term "carrier", as used herein, refers to chemical compounds or agents that facilitate the introduction of a compound disclosed herein into cells or tissues.

The terms "co-administration" or "combined administration" or the like, as used herein, are understood to include the administration of selected therapeutic agents to the same patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

The term "dermatological disorder" as used herein refers to a skin disorder.

Such dermatological disorders include, but are not limited to, proliferative or inflammatory skin disorders such as atopic dermatitis, bullous disorders, collagen diseases, contact dermatitis, eczema, Kawasaki disease, acne vulgaris, Sjögren-Larsson syndrome, keratosis pilaris, basal cell epithelioma, and hives.

The term "diluent" as used herein refers to chemical compounds used to dilute a compound disclosed herein prior to delivery. Diluents may also be used to stabilize the compounds disclosed herein.

The terms "effective amount" or "therapeutically effective amount" as used herein refer to a sufficient amount of a compound disclosed herein administered that will alleviate to some degree one or more symptoms of the disease or pathological condition being treated. The result may be a reduction and/or amelioration of the signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an "effective amount" for therapeutic applications is an amount of a composition comprising a compound as disclosed herein necessary to provide a clinically significant reduction in disease symptoms.

An appropriate "effective" amount in any given case can be determined using techniques such as dose-escalation studies.

The terms "enhance" or "enhance" as used herein mean an increase or prolongation of either the intensity or duration of a desired effect. Thus, with respect to enhancing the effect of therapeutic agents, the term "enhancement" refers to the ability to increase or prolong, or in intensity or duration, the effect of other therapeutic agents on the system. "Enhancing effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

The terms "fibrosis" or "fibrous disorder" as used herein refer to conditions that follow acute or chronic inflammation and are associated with abnormal accumulation of cells and/or collagen and include, but are not limited to, fibrosis of individual organs or tissues such as the heart, kidney, joints, lungs, or skin, and includes disorders such as idiomatic pneumosclerosis and cryptogenic fibrosing alveolitis.

The term "iatrogenic" as used herein means a condition, disorder, or disease created or aggravated by medical or surgical therapy.

The term "immunologically effective amount" as used herein means the administration of a sufficient amount to an individual, either as a single dose or as part of a series, which is effective in treating or preventing an immunological disease or disorder. This amount varies depending on the health and physical condition of the individual to be treated, the age, the taxonomic group of the individual to be treated (eg, primate - non-human, primate, etc.), the ability of the individual's immune system to synthesize antibodies, the degree of desired protection, the composition of the vaccine, the doctor's assessment of the medical situation, and other important factors. The number is expected to fall within a relatively wide range that can be determined by routine testing.

The term "inflammatory disorders" as used herein refers to those diseases or conditions characterized by one or more of the signs of pain (inflammation, from the production of harmful toxic substances and nerve stimulation), fever (fever, from vasodilatation), redness ( redness, from vasodilatation and increased blood flow), edema (swelling, from excessive inflow or limited outflow of fluid), and loss of function (impairment of functioning, which may be partial or complete, temporary or permanent). Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, diffuse, exudative, fibrinous, fibrous, central, granulomatous, productive , hypertrophic, interstitial, metastatic, necrotic, obliterating, parenchymal, plastic, productive, proliferative, pseudomembranous, purulent, sclerosing, serous-fibrous, serous, simple, specific, subacute, purulent, toxic, traumatic and/or ulcerative inflammation. Inflammatory disorders additionally include, without limitation, those that damage blood vessels (polyarteritis, temporal arteritis); joints (arthritis: crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's); gastrointestinal tract (Crohn's disease); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).

The term "modulate," as used herein, means to interact with a target, either directly or indirectly, in such a way as to alter target activity, including, by way of example only, increasing target activity, inhibiting target activity, limiting target activity, or enhancing target activity .

The term "modulator" as used herein refers to a molecule that interacts with a target either directly or indirectly. Such interactions include, but are not limited to, agonist or antagonist interactions.

The terms "ocular disease" or "ophthalmic disease" as used herein refer to diseases affecting the eye or eyes and potentially the surrounding tissues. Ocular or ophthalmic diseases include, but are not limited to, conjunctivitis, retinitis, scleritis, uveitis, allergic conjunctivitis, vernal conjunctivitis, papillary conjunctivitis, and cytomegalovirus (CMV) retinitis.

The term "pharmaceutically acceptable" as used herein refers to a material such as a carrier or diluent that does not nullify the biological activity or properties of the compounds disclosed herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

The term "pharmaceutically acceptable salt" as used herein refers to a composition of a compound that does not cause significant irritation in the organism to which it is administered and does not nullify the biological activity or properties of the compounds disclosed herein.

The term "combination" or "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, for example, such as a compound of Formula (I) and an additional therapeutic agent, are both administered to the patient together in the form of a single substance or dose. The term "unfixed combination" means that the active ingredients, for example, such as a compound of Formula (II) and an additional therapeutic agent, are both administered to the patient as separate substances or together, simultaneously or sequentially without specific time limits, such administration providing therapeutically effective levels 2 compounds in the patient's body. The latter term also refers to combination therapy, for example, the introduction of three or more active ingredients.

The terms "composition" or "pharmaceutical composition" as used herein refers to a mixture of at least one compound, such as a compound of Formula (I) disclosed herein, with at least one, and optionally more than one, other pharmaceutically acceptable compounds. chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or fillers.

The term "prodrug", as used in this description, refers to an agent that is converted into the parent drug ip mimo. A non-limiting example of a prodrug of a compound disclosed herein is a compound disclosed herein that is administered as an ester, which is then metabolically hydrolyzed to a carboxylic acid, an active substance, upon intracellular delivery.

An additional example of a prodrug is a short peptide attached to an acidic group, where this peptide is metabolized to reveal an active residue.

The term "respiratory disease" as used herein refers to diseases affecting the organs involved in breathing, such as the nose, throat, larynx, trachea, bronchi and lungs.

Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, status asthmaticus, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, pediatric asthma, adult asthma, cough asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, chronic allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.

The term "subject" or "patient" as used herein includes mammals and non-mammals.

Examples of mammals include, but are not limited to, humans, chimpanzees, apes, cattle, horses, sheep, goats, pigs; rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like.

Often the subject is a human, and may be a human diagnosed in need of treatment for a disease or disorder disclosed herein.

The term "TC modulator", as used herein, refers to a compound that modulates the TC receptor.

The term "TIC disease" or "disease or disorder associated with TI KE activity", as used in this description, refers to any disease state associated with the Toll-like receptor.

Such diseases or disorders include, but are not limited to, infectious diseases, inflammatory diseases, respiratory diseases, and autoimmune diseases such as, but not limited to, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS5), disease Crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus.

The term "therapeutically effective amount" as used herein refers to any amount of a compound which, when compared to a subject receiving no such amount, results in improved treatment, cure, prevention, or amelioration of a disease. , disorder, or side effect, or decrease in the rate of progression of the disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

The terms "treating," "treating," or "treatment," as used herein, refer to methods of mitigating, alleviating, or ameliorating the symptoms of a disease or pathological condition, preventing the occurrence of additional symptoms, reducing the intensity of, or preventing the occurrence of underlying metabolic causes of the symptoms. , inhibiting a disease or pathological condition, stopping the development of a disease or pathological condition, ameliorating a disease or pathological condition, causing regression of a disease or pathological condition, alleviating a condition caused by a disease or pathological condition, or stopping the symptoms of a disease or pathological condition either prophylactically and/or therapeutically.

Other objects, features, and advantages of the methods, compositions, and combinations disclosed herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples showing specific embodiments are provided for illustration purposes only.

Description of the best implementation options

Provided herein are compounds and their pharmaceutical compositions that are Toll-like receptor (TIC) modulators. In certain embodiments, certain compounds disclosed herein and their pharmaceutical compositions are Toll-like receptor agonists. In other embodiments, such compounds and their pharmaceutical compositions are TI K7 agonists.

In other embodiments, such compounds and their pharmaceutical compositions are agonists

TI K8. In other embodiments, such compounds and their pharmaceutical compositions are agonists of both TI K7 and TI! K8, that is, such compounds and their pharmaceutical compositions, are dual agonists of TIK7 and TI Kv.

Provided herein are compounds, pharmaceutical compositions, and methods of treating and/or preventing diseases and/or disorders associated with TI EC activity. In certain embodiments, such

TI -Vs are TI K7 and TI K8.

TIC modulators provided herein include compounds having the structure of Formula (I) and their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers:

Provided herein are compounds, pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers having the structure of Formula (1):

Bey xx

Formula (I) in which:

X represents M or CM(B'B2); Xg is M or CM(K'B2), provided that when X' is CM(K'NVZ), then X2 is M;

ХЗ is M or SIK;

X" represents M or SVZ; and X5 represents -CH/-SIVe-, -C87-M- or -M-SIV-;

A and B? each is independently selected from such as:

C 1 -haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 -heterocycloalkyl, wherein each of the groups such as:

Svheterocycloalkyl radicals K' and B? is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, -О, С1-Св alkyl, С--Свhaloalkyl, С--Свлаксокы group, Сз-

Swcycloalkyl, -OH8, -С(О)НЯ, -ОС(О)Н8Я, -С(О0)ОН8, -М(ВУ)2, -С(О)М(ВУ)», C3-Swheterocycloalkyl, - ( 0288. », C1-

Svhaloalkyl and C/-Svhaloalkoxy group, and where each of the aryl and heteroaryl groups of the radicals KE" and Kg is optionally substituted with 1-3 substituents independently selected from such as: halogen, -CM, Ci-Cv alkyl, WITH-

Seghaloalkyl, Ci-Svaloxy group, C3-Cvcycloalkyl, -OH8, -C(0)88, -OC(O)H8, -C(0O)OH8, -M(BZ)". -

C(O)M(AU)», C3-Swheterocycloalkyl, -5(0)2H88, -5X0)2M(AU)2, -MA?5(O)2H8, - P(IFOHONV)», -POR(OHOVU ", -

GR(IOHOV'9)", -OG P(IFHOK9)", C1-C8haloalkyl and C1-C8haloalkyloxy group, or K' and K2 each independently represent C1-C8alkyl, which may be substituted as described above, and, taken together with the M atom to which they are attached, form an optionally substituted C3-

Svheterocycloalkyl;

VZ and KU are each independently selected from the following: H, halogen, Si-Svalkil, Ce-Svalken, Sg-Svalkin, C1-

S-heteroalkyl, C-Swhaloalkyl, C-Swallowoxy group, C-Swhaloalkyl group, aryl, heteroaryl, C3-

Sw-cycloalkyl, and C3-Swheterocycloalkyl, where each of the groups, such as: C-Swalkyl, C-Swheteroalkyl, C-Swhaloalkyl, C-Swallowoxy group, C1-

The α-haloalkyl group, C3-C8cycloalkyl, or C3-C8-heterocycloalkyl of the ECZ and K9 radicals is not necessarily substituted by 1-3 substituents independently selected from such as: halogen, -СМ, -О, В, -

ОВе, -С(0)88, -ОС(О)Н8, -С(О)О 8, -М(ВУ)», -С(О)М(ВУ)», -5Х0)288, -5( 0)2 M(VU)2 and -MAZ5(O)2HB, and where each of the aryl and heteroaryl groups of the KZ and Ke radicals is optionally substituted with 1-3 substituents independently selected from such as: halogen, - СМ, В", -ОН8, -С(О)НВ, -

ОС(О)Н8, -С(О)ОНВ, -М(ВУ)2», -С(СО)М(АУ)2, -(О)288, -6(0)2М(АУ)» and -MA?5(O)2H8;

B" and K5 are each independently selected from the following: H, halogen, -"С(О)ОВ, -С(О)В8", -С(О)М(БВ), -

М(В"В2), -МЖ(ВУ)", -МНИ(ВУ)", -587,. -"СНапОВ, -(СНа)аВ", -СА8, -8То, -О1 КВ, -ОСАТО, bi -Swalkill, Si-

Swheteroalkyl, C1-Swhaloalkyl, C3-Swalkene, C0-Swalkyne, C1-Swallowoxy, C1-Swhaloalkyl, aryl, heteroaryl, C3-Swcycloalkyl, and C3-Swheterocycloalkyl, wherein each of the groups such as: C1-Swalkyl, C--Swheteroalkyl, C-Swhaloalkyl, Soe-Swalken, Sg-Swalken, Si-

Alkoxy group, C1-C8haloalkyl group, C3-C8cycloalkyl, or C3-C8heterocycloalkyl, radicals EC" and

AND? is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, -0, -МО», -Б87, -ОН8, -Ф(О)Н88, -ОС(О)Н8 , -S(O)OV8, -M(VU)", -RIOHOVU)2, -OR(OKHONV)", -

Р(IFOHONV"9)", -OR(IFOHOV'O9)", -С(О)М(АУ)", -5I(АВ)з, -5(О)2Н8, -5(0) АВ, - 5X0)2M(AU)»2, and -MA?5(O)2HB, and where each of the aryl and heteroaryl groups of the radicals KK? and EK? is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, -В87, -ОВ8, -С(О)Н8, -

ОС(О)Н8, -С(О)ОНВВ, -М(ВУ)2, -Р(ИОХОВУ)», -OR(IFHONVU)», -Р(IFHOV З)», -OR(ОХОВ'О)» , -С(О)М(ВУ)», -

ZI(B8)z, -5(0)288, -5(O)H88, -5(0)2M(AU)", and -MAZ5(O)2 HB; or EZ and K", or K- and KE", or P and He, when located on adjacent ring atoms, can optionally be connected together to form a 5-6b-membered ring, where 5-6b- -the ring is optionally replaced by K"/; each I. is independently selected from such as: connection, -««O(СНг)т)-, Si-Swalkyl, So-Swalkenylene and So-

Swalkynylene, where each of the groups such as: Si-Swalkyl, Co-Swalkynylene and Co-Swalkynylene of the H radical.

optionally substituted with 1-4 substituents independently selected from such as: halogen, -

Ве -ОНВ8, -М(ВУ)2, -Р(ОХО ВЗ)», -ОР(ОХО ВЗ)», -Р(IFOHХХОВ' 9)», and -OR(ХОХОХО)»;

B' is selected from such as: H, C:-Salkyl, aryl, heteroaryl, C3-C8cycloalkyl, C1-C8heteroalkyl, C1-

C-haloalkyl, Co-Swalkene, C-Swalkene, C-C-Swalkoxy group, C-Swhalo-Alkoxy group, and cC3-

Swheterocycloalkyl, where each of the groups such as: C1-Swalkyl, C3-Swcycloalkyl, C1-Swheteroalkyl, C1-Swhaloalkyl, Se-

Svalken, Cg2-Svalkin, C-Svalkoxy group, C-Swhaloalkyl group, or C3-Swheterocycloalkyl, the K" radical is optionally substituted with 1-3 B"C groups, and each KZ is independently selected from such as: halogen, - CM, -0, -|Г Ve, -HOV, -OG 8, -Г8о, -GOVо, -ОГАо, -ув8, - ОВ8, -OG 8, -И 588, -И 5АО, -ЙФ(О)Н8 . -

MAYA, -EMAUVO, - S(O)M(AU)", -I (0288, -i (0), - S(O)MAVON, -MAS(O)VV, - MAS(OOVV, -

ГФ(-М-ОВВ)АЯ, - С(-МН)-МНОНВУ, -МНО(-МН)МН», -И5(0)2М(АУ)2, -О1И 5(О)2М(ВУ)» -IMAR5(O)2B8, -

And C(O)MAUI M(AZ)", - P(FHOVZ)", -GOR(OHOVV)", - P(FOHOV'9)" and -ОЙ P(IFHOK 2; where each of the aryl and heteroaryl groups of the radical B" is optionally replaced by 1-

From VZ groups, and each KZ is independently selected from the following: halogen, -SM, -I 8, -HONV, -O1 B, -I VO, -

ГО, -О1 о, -IA88, - ОВ, -О1 8, -1588, -158', - С(О0)88, -ОГС(О)К - (ОО, - С(О)ВО, -

GOS(OONV, - S(O)MAYAA", -I S(O)MAyaAV, -I M(AU)", -EMAYAVV, -G MAYA, - SOVA)", -I5(0)2Н88, -

I5B(O)NYA, - C(O)MAZON, -I/MAZS(O)NU, -/МАС(ОВВ, -Сб(-М-ОВ8)АВ, -С(-МН)-МНОНВ, /-

МНО(-МН)МН», -5(0)2М(АУ)2, -ОИ 5(О)2М(НЯ)», -ИМАБ(О)2Н8, -I С(О)MARI М(ВУ)2 , -IR(OHOVV)", -

HOR(OKHONV)", -I RIOHOV'9)" and -OYI R(IFOHOK Z)"; each KZ is independently selected from such as: Н, -СН(В'9)», Si-Svalkil, So-Svalken, Sgo-Svalkin, Si-

C:-Swhaloalkyl, C:i-Swallowoxy group, C.:-Swheteroalkyl, C3-Swcycloalkyl, C2-Swheterocycloalkyl, C1-

Sw-hydroxyalkyl and C1-Swhaloalkyl group, where each of the groups such as: C1-Swalkyl, Co-Swalkene, C2-

Svalkin, C-Swheteroalkyl, C-Swhaloalkyl, C-Swallowoxy group, C3-Swcycloalkyl, -: C2-

Sv-heterocycloalkyl, Ci-Svhydroxyalkyl and Ci-Svhaloalkyl group, the KZ radical is optionally substituted with 1-3 substituents independently selected from such as: -СМ, В", -ОВ", -58, - сС()В ", -ОС(О)В8", -С(ОМ(АУ)», -С(О)О8" -МАС(О)В", -МАЗВЯ, -МА"TV:, -М(ВУ)2, -OVYA, -OVYA, -

С(О)МА" В, -С(О)МА"ЧОН, -550)28", -5(0)8А", -5(О)2МА"А, -MALO(О)2А", -ROHOV 2", and -

ОР(ООХОВ" )"; each K? is independently selected from such as: Н, -С(О0)Н8, -С(О)ОН8, -С(О)В8Я, -Ф(О00)О НО, -5И( B8)", - (0289, -C1-C8 alkyl, C1-C8 heteroalkyl and C3-C8 cycloalkyl, or each 2? independently represents C1-

Alalkyl, which together with M, to which they are attached, forms C3-Swheterocycloalkyl, where C3-

The s-heterocycloalkyl ring optionally contains an additional heteroatom selected from M, O and 5, and where each of the groups such as:

Svheterocycloalkyl, radical BK? is optionally substituted with 1-3 substituents independently selected from such as: -СМ, В", -ОВ", -58", -Ф(О)8", -ОС(О)В", - S(O)OV", - MA "V", -

C()MA" B, -C(O)MA"CHON, -5(O)2A", -5(O)8", -5(O)2MA" B, -MA"TO(O)2B" , -RIOHOV")", and -

OP (Protection")"; each KK"? independently selected from: aryl, C3-Sw-cycloalkyl, C3-Sw-heterocycloalkyl and heteroaryl, where aryl, C3-Sw-cycloalkyl, C3-Sw-heterocycloalkyl and heteroaryl groups are optionally substituted with 1-3 substituents selected from such as: halogen , -H8, -ОНВ, -

Be, -HOVe, -M(VU)2, -MAZS(O)H8, -MA?СО»2 HB, -СО2Н8, -С(О)В88 and -С(О)М(ВU)»;

B" and "2 are independently selected from the following: H, C1-C6alkyl, C1-C1-C6 heteroalkyl, C1-C6-haloalkyl, aryl, heteroaryl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl, wherein each of the groups such as : Ci-Swalkyl, Ci-Swheteroalkyl, Ci-Swhaloalkyl, C3-Swcycloalkyl and C3-

Svheterocycloalkyl, radical KK"! and KK! is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, -0, 88, -ОБ8, -С(О0)Н8Я, ОС( О)Н8, -С(О)ОНВВ, -М(ВУ)», -

MAZS(O)NU, -MAZS(O)ONB, -C(O)M(VU)2, C3-Swheterocycloalkyl, -5(0)2H88, -550)2M(AU)2, -MA"5(O )2NU, University of

C-haloalkyl and C-Ci-Chaloalkyl group, and where each of the aryl and heteroaryl groups of the radicals KE" and B" is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, 88, -ОН8, -С(О)НВ, -

ОС(О)Не, -С(О0)ОН8, -М(ВУ)», -«МAZО(О)Н8, -МАЗС(О)ОН8, -С(О)М(ВУ)», C3-Swheterocycloalkyl, -5(0)288, - 5(0)2M(AU)", -MA?5(O)2H8, C1-Swhaloalkyl and C1-Swhaloalkyl group, or K" and "2 each independently represents C1-Swalkyl and taken together with the M atom to which they are attached, form an optionally substituted C3-Swheterocycloalkyl ring, optionally containing an additional heteroatom selected from M, O, and 5;

Ring A is aryl or heteroaryl, where the aryl or heteroaryl groups of Ring A are optionally substituted with 1-3 BA groups, where each KA" is independently selected from such as: halogen, -H8, -87, -O87, - ON8, -VTO. -О8То, -588, -МО", -СМ, -М(ВУ)2, -МАЗС(О)Н8, -МА?С(5)НА8, -

MAZS(O)M(VU)", -MAS(5)M(VU)", -MASO2H8, -MAMAZS(O)B8, -MA"MAZS(O)M(AU)", -MA"MA?SO »VV, -

С(О)С(О)Н, -С(О)СНеС(О)ВЯ, -СО2Н8, -«(СНег)пСО»НУ, -С(О)Н8, -С(5)Н88, -С( O)M(AU)», -С(5)M(AU)», -

ОС(О)М(НУ)", -ОС(О)Н8У, -С(О)М(ОНВ)НВ, -С(МОНВ)АВ, -5(0)288, -5(0)388, - 502М(Н82)2, -5(0)Н8, -

MA?BO2M(VU)2, -MA?5O»NYA, -P(IFOVU)", -OR(OKHOVU)", -P(IFKHOV'O)", -OR(OKHOV'O)", -MSHCHONUVV, -

Ссн-СснеО»не, -С(-МН)-М(АУ)», and -«СНг)аМнНО(О)НУ, and two adjacent substituents on Ring A can be connected to form a 5-6-membered a ring that can contain up to two heteroatoms as ring members; n is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7 or 8; each t is independently chosen from such as: 1, 2, 3, 4, 5 and 6, and

It represents 1,2,3,4, 5,6, 7 or 8.

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (1-A), hee, She

Ho hu - M

MN

Formula (I1-A).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (eg, hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (1-B), 4 / more

HO

M - 3 -d-

H M MN".

Formula (II-B).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (I),

Kz she "F,

Kk M M MN",

Formula (II).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (eg, hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (II),

Kz n

Zkh lk v. M

MN"

Formula (I).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (eg, hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (IM),

Kz and SA)

Pho! in

Kb MN"

Formula (IM).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (M),

Kz va SA) 9 in M MN" ke

Formula (M).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (MI),

Kz tea

Ex

Co

BC 0 MN"

Formula (MI).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (MI),

In M o s rya in M

MN"

Formula (MINE).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (MIP),

And M and

From DM

Co

Be 0 MNo

Formula (MIP).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (IX),

Kz i rya M a

Mn.

Formula (IX).

In certain embodiments of the compounds of Formulas (1)-"IX), Formulas (I-A) and Formulas (I-B), Ring A is selected from: phenyl, naphthyl, fluorenyl, indenyl, azulenyl and anthracenyl, each of which is optionally substituted with 1-3 B" groups, where each B" is independently selected from such as: -H8, -87, -ОВ8", -ОВ8, -8О. -О08Т9, -588, -МО», -СМ, -М(ВЗ)2, -МАУС(О)Н8, -МАС(5)А88, -МАС(ОМ(ВУ)», -

MAZS(5)IM(AU)", -MAYASO»VYA, -MAZMA?S(O)NYA, -MA"MAS(O)M(AU)", -MAyaMASO»VU, -S(O0)S(O )H88, -

С(О)СНоС(О)ВВ, -СО2Н88, -«(СНаг)аСО»вУ, -С(О0)Н88, -С(5)88, -С(О)М(Б8У)», -С( 5) M(VU)2, -OS(OM(VU)", -

ОС(О)НЯ, -С(О)М(ОВУ)АЯ, -С(МОНВ)АЯ, -5(0)288, -5(0)388, -502М(В)2, -5(0) H8, -MA?5BO2M(VU)", -

MAO", -P(IOHO VV)", -OR(IFOHO NU)", -P(FKHON 9)", -OR(OHOV'O)", -SHCHO HB, -"SN-SNSO"NU, -S (-MN)-

M(VU)2, and -""СНе)оМНО(О)АВ. In other versions of the embodiment of the compounds of Formulas (1I)-(IX), Formulas (I-A) and

Formulas (I-B), Ring A is phenyl or naphthyl, each of which is optionally substituted with 1-3 B" groups, where each RA is independently selected from: -H8, -B87, -ОВ" , -ОН8, -Но, -ОВ/О, -

ZAV -MO", -SM, -M(VU)", -MAZS(O)H8, -MA?S(5)A8, -MAZS(O)M(AU)", -MAZS(B)UM(NU) », -MAZSO»VV, -

MA?MA?S(O)NYA, /-MAZMAYAS(O)M(AU)", -MA"MA?SO»VAU, -B(0)S(O0)88, -S(O0)SNS(O )NAU -СО288, 0 - (СНг)обО»вУ, -С(О)Н88, -С(5)88, -С(О)М(АУ)2, -С(5)М(8У)2, -OS(O)M(VU)2, -OS(O)NYA, -S(OMOVUNU, -

С(МОВУ)АЯ, -5(0)288, -5(0)з388, -502М(АУ)2, -5(0)Н88, -МАЗ5О2М(ВУ)», -MA?5BO2gNYA, -P(IOHONU )»,

ОР(ОХОНВВ)», -Р(ФХОВ'О)», -ОР(ОМДОВ'О)», -МЩ(ОВУАЯУ -СН-СНСО»НУ, -С(-МН)-М(ВУ)», and - (SNhomMne(o)vv.

In certain embodiments of compounds of Formulas (1)-"IX), Formulas (I-A) and Formulas (I-B), Ring A is selected from the following: benzofuranyl, benzofurazanyl, benzoxazolyl, benzopyranyl, benzthiazolyl, benzothienyl, benzazepinyl, benzimidazolyl ) . and tetrazolyl, each of which is optionally substituted with 1-3 B" groups, wherein each

VAH is independently chosen from the following: -Н8, -87, -ОВ", -ОВ8, -8'О, -ОВ8'О, -5А8, -МО", -СМ, -М(ВЗ)», -

MAZS(O)NYA, 0 -MARS(B)AYA, 0 -MAS(O)M(A?)", 0 -MAZS(BM(AU)", 0 -MASO2NU, 0 -MAMAYAS(O)VV, SS -

MAZMAS(OM(AU)2, -MA?MA?SO»gVU, -С(О0)С(О)Н88, -С(О)СНоС(О)ВВ, -СО2Н88, -(СНг)ибОгве, -С (O)H8, -

С(5)АЯ, -С(О)М(ВУ)2, -С(5)М(ВУ)2, -ОС(ОМ(ВУ)», -ОС(О)ВНЯ, -С(О)М (OVV)АЯ, -С(МОВУ)АЯ, -5(0)288,. -

З(О)зА8, -502М(82)2, -5(0)Н88,. -MA?5O2gM(NU)2, -MA?5O»NV, -P(IHOVU)2, -OR(PHOH(OVV)", -P(OHOV 9)", -

ОР(ОХОНВ'О)», -МОНВ)НЯ, -СН-СНСО»ВВ -С(-МН)-М(ВУ)», and -(СНg)МНО(О)НУ. In other variants of the embodiment of the compounds of Formula (1)-("IX), Formula (I-A) and Formula (I-B), Ring A is selected from such as: pyridyl, benzo|1,Z|dioxol, thienyl, benzothienyl, benzofuranyl, or indolyl, each of which is optionally substituted with 1-3 B" groups, where each K" is independently selected from such as: -H8, -B"7, -ОВУ, -

ОВ, -8о, -ОВо, -5588, -МО», -СМ, -М(ВУ)», -МАЗС(О)В8, -МАУС(5)А8, -МАС(ОМ(ВУ)2, -МАЗС (ZIM (VU) ", -

МА?СО»В8, -МА?МАЯС(О)Н8, -"MA"МАС(О)М(АУ)", -"МА"МAZСО»НВ, -С(О)С(О)Н8, -С (О)СНгС(О)НУ8, -СО2Н88, -(бНг)нбО»ве, -С(О)88, -С(5)Н88, -С(О)М(АУ)2, -С(Б) М(ВУ)2, -«ОС(О)М(ВУ)2, -ОС(О)Н8Я, -С(О)М(ОВУНУ, -

С(МОВУ)АЯ, -5(0)288, -5(0)з388, -502М(АУ)2, -5(0)Н88, -МАЗ5О2М(ВУ)», -MA?5BO2gNYA, -P(IOHONU )»,

ОР(ОХОНВВ)», -Р(ФХОВ'О)», -ОР(ОМДОВ'О)», -МЩ(ОВУАЯУ -СН-СНСО»НУ, -С(-МН)-М(ВУ)», and - (SNhomMne(o)vv.

In certain embodiments of compounds of Formulas (1)-"IX), Formulas (I-A) and Formulas (I-B), Ring A is selected from such as: phenyl, thienyl, and pyridyl, and in other embodiments such phenyl, thienyl and pyridyl groups are optionally substituted with 1-3 В" groups, where each КЕ" is independently selected from such as: -Н88, -87, -ОВ8, -ОВ8, -ВО, -ОВ8О, -588, - MO», -SM, -M(VU)2, -MAUS(O)NU, -

МА?С(5)А8Я, -MAZS(O)M(VU)", -MAZS(5)M(AU)", -MASO2N, -MAMAYAS(O)NYA, -MAMAS(OM(VAU)", -

MA?MA?СО2НВ, -С(О)С(О)Н8, -С(О)СНгС(О)Б8, -СО»2Н88, -(СНаг)аСОгве, -С(О)Н88, -С(5 )88, -S(O)M(AU)", -

S(B)M(AU)", -OS(OM(AU)", -OS(O)NYA, -S(O)M(OVU)AV, -S(MOVV)AV, -5(0)288 , -5(0)z388, -502M(AU)", -

5(0)H8, -MA?5O2M(AU)2, -MA?5O2NU, -RIOJO UNIVERSITY)», -OR(FOHO NU)», -Р(ХХОВ 9)», - OOR(ОХОВ' 9)» , -SHOVUNU, -

Ссн-СснеО»Нне, -С(-МН)-М(ВУ)», and -СНг)оМне(О)вВ.

In certain embodiments of the compounds of Formulas (1)-(IX), Formulas (1I-A) and Formulas (I-B), Ring A is phenyl, optionally substituted with 1-3 B" groups, where each EC " are independently chosen from such as: -H8, -B87, -ОВ8, -ОН8, -8О, -ОВТО, -588, -МО», -СМ, -М(ВУ)2, -МАЗС(О)Н8У, - MA»S(5) AV, -

MAS(O)M(AU)", -MAUS(BIM(AU)", -MASO»B8, -MAMAZS(O)B8, -MA"MAS(O)M(AU)", -MA"MA?SO »NVV, -

С(О)С(О)Н, -С(О)СНеС(О)ВЯ, -СО2Н8, -«(СНег)пСО»НУ, -С(О)Н8, -С(5)Н88, -С( O)M(AU)», -С(5)M(AU)», -

OS(O)M(VU)", -OS(O)NYA, -S(O)M(OVU)AYA, -S(MONV)AV, -5(0)288, -5(0)388, - 502M(85)", -5(0)H8, -

MA?ZBO»M(NU)", -MA?5O»NU, -R(IFHOVU)", -OR(IOHONVU)", -RIFHOV'O)", -OR(IOHONV'O)", -MSH( ONUAV, -

Ссн-СснеО»Не, -С(-МН)-М(ВУ)», and -СНазМНО(О)НВУ. In certain embodiments of compounds Formula (1)-(IX),

Formulas (I-A) and Formulas (I-B), Ring A is a pyridyl, optionally substituted with 1-3 BA groups, where each БЕ" is independently selected from such as: -H8, -87, -ОВ "7, -ОВ8, -ВІЕ, -ОВ'О, -588, -MO", -

SM, -M(VU)2, -MAYAS(O)H8, -MAUS(5)A8, -MAS(O)M(AU)2, -MAZS(5)M(A)2, -MA"SO" B8, -MA?MA"S(O)NU, -

MAMAS(O)M(AZ)", -MA"MASO»Ve, -С(О)С(О)Н8, -С(О)СНоС(О)В, -СО288, -СНаг)бО»ve, -С(О)Н8, -

С(5)АЯ, -С(О)М(ВУ)2, -С(5)М(ВУ)2, -ОС(ОМ(ВУ)», -ОС(О)ВНЯ, -С(О)М (OVV)АЯ, -С(МОВУ)АЯ, -5(0)288,. -

З(О)зА8, -502М(82)2, -5(0)Н88,. -MA?5O2gM(NU)2, -MA?5O»NV, -P(IHOVU)2, -OR(PHOH(OVV)", -P(OHOV 9)", -

ОР(ОХОВ'9)", -ШЧОНУН8, -"СНАСНОСО»НВВ, -"С(-МН)-М(ВУ)", and -""СНгзаМнНОе(С)НВ.

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (X), 7 vo - 2 M

In M

MH,

Formula (X).

In certain embodiments, compounds of Formula (X), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (X-A),

In I - lake

In

In M

MN.

Formula (X-A).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (eg, hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (XI),

BA ve

In cha r tsula

In M

MH,

Formula (XI).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have a structure of Formula (XII) or Formula ( HIII),

in

In Me:

M - M and M her M 5

Mn, Mn,

Formula (ХИЙ) Formula (ХП).

In certain embodiments of the compounds Formula (I), (I-A), (I-B) and (1)-(XI), B? and Re, when present, are independently selected from such as: H, halogen, -С(О)ОВ, -С(О)8, -С(О)М(А" 82), -М(АВ 2), - M(AZ)", -

MNMA)", -587,. -"СНаг)пО Б, -(СНг)пив?, -Н8, -8То, -О1 КВ, -ОГ Ко, bi-Svalalkyl, C-Swheteroalkyl, C-

Svhaloalkyl, Co-Svalkene, Co-Svalkyne, C--Svalkoxy group, C-Svalhaloalkyl group, aryl, heteroaryl,

C3-Swcycloalkyl, and C3-Swheterocycloalkyl, where each of the groups, such as: C1-Swalkyl, C1-Swheteroalkyl, C1-

C 1 -Shaloalkyl, C 2 -Swalkene, C 2 -Swalkyne, C--Swalkoxy group, C 3 -Swhaloalkyl group, C 3 -C 2 cycloalkyl, or

C3-Swheterocycloalkyl, radical EB" and EK? is optionally substituted with 1-3 substituents independently selected from such as: halogen, -CM, -0, -MO", -8", -ОВ8, -С (O)H8, -OC(O)H, -C(O)OH, -

M(VU)", -RIFKHONVZ)2, -OR(FOHOVVZ)", -P(OKHOV9)2, -OR(OKHO VO)", -S(O)M(VAZU)", -5I(A88)z . is optionally substituted with 1-3 substituents independently selected from such as: halogen, -СМ, -87, -ОВН8, -С(0)Н88, -ОС(О)НЯ, -С(О0)ОВ8 , -M(VZ)2, -P(IOHONVZ)", -OR(IOHOVU)", -R(FHOV'O", -

ОР(ОХОВ'О)», -С(О)М(ВУ)», -5(А8)з, -5(0)288, -5(0)Н88, -5(0)2 М(ВУ) 2, and -MAU5(O)2NU. In other embodiments, KZ and NK", or K- and P", or EE and KU, when located on adjacent ring atoms, can be optionally bonded together to form a 5-6b-membered ring, where 5-6b--the ring is optionally substituted with K"7.

In certain embodiments of the compounds Formula (I), (I-A), (I-B) and (1)-(XIII), each I! are independently selected from such as: bond, -"O(CHg)t)-, Si-Svalkyl, Co-Svalkenylene and C0-Svalkynylene, where each of such as: Si-Svalkyl, Cg-Svalkenylene and C2o-Svalkynylene radical It is optionally substituted with 1-4 substituents independently selected from such as: halogen, -Н8, -ОН8, -М(ВУ)2, -Р(ИОХОНВ)», -ОР(ОХОНВ)», -Р (OKHOV'9)", and -OR(OKHOV' 9)".

In certain embodiments of compounds of Formula (1), (I-A), (I-B) and (1)-(XI!), B" and P", when present, are independently selected from such as: H, halogen, -"С(О)ОВ, -С(О)8", -С(О)М(В В), "ШЧА В", -М(ВУ)", -

MNMA)", -587,. -"СНаг)пО Б, -(СНг)пив?, -Н8, -8То, -О1 КВ, -ОГ Ко, bi-Svalalkyl, C-Swheteroalkyl, C-

Svhaloalkyl, Co-Svalkene, Co-Svalkyne, C--Svalkoxy group, C-Svalhaloalkyl group, aryl, heteroaryl,

C3-Swcycloalkyl, and C3-Swheterocycloalkyl, where each of the groups, such as: C1-Swalkyl, C1-Swheteroalkyl, C1-

Svhaloalkyl, Co-Svlkene, Cg-Svlkyne, C--Svlkoxy group, C--Svhaloalkyl group, Cz-Svcycloalkyl, Cz-

Suheterocycloalkyl, aryl and heteroaryl radicals K" and EE" are optionally substituted with 1-3

IN".

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of these isomers have the structure of Formula (XIM), and A 1 t 0-3 her M:

A sh

E M

MH,

Formula (CHEM).

In certain variants of the embodiment of the compounds of Formula (1), (I-A), (I-B) and (1)-(KHIM), B" are selected from such as: H,

C:i-Salkyl, C3-Swcycloalkyl, C3-Swheteroalkyl, C1-Swhaloalkyl, Co-Swalkene, Co-Swalkyne, C1-Swallowoxy, C1-Swhaloalkyl and C3-Swheterocycloalkyl, wherein each of the groups such as: C- Svalkil, Sz-

Swcycloalkyl, C1-Swheteroalkyl, C1-Swhaloalkyl, C-Svalkene, C2-Svalkyne, C-Svaloxy group, C1-

The α-haloalkyl group, and C3-α-heterocycloalkyl, radical K" is optionally substituted by 1-

From VZ group, and each K"Z is independently chosen from the following: halogen -SM, -О, -I VU, - ОВ, -OG KU, -I VO, -

ОВ, -О01 Ко, -И88, -ОВ8, -О1 8, -1588, -И58'О, - С(О0)88, -ОИ С(О)Н8, - (0), - С(О)ВО , -

GOS(OONV, - S(O)MAUVA", - S(O)MANV, -I M(VU)", "MAV -I MAV, - S(OM(VU)", -I (0288, -I ( 0) HB,

-YHF(O)MAZON, -IMAS(O)NYA, - MAS(ONVV, - С(-М-ОВ8)А8, - С(-МН)-МНОВ8, -МНО(-МН)МН», С -

I 5(O)2M(AU)2, -O1 5B(O)2M(AU)2, -IMA?B(O)2NYA, -I S(O)MAR (VU), -GRIOHOVU)", -OR (PROTECTION)", -

GR(IFOHOV"9)" and -OI R(IOHOV'9)".

In certain embodiments of the compounds of Formula (I), (I-A), (I-B) and (1)-(CHM), B" represents an aryl or heteroaryl group, optionally substituted by 1-3 BZ groups and each short circuit is independently selected from such as: halogen, -SM, -I 8, -Г ОВ, -ОГ Не, -Г АТО, - 089, -ОКА о, -И 88, - ОБ8, -ОГ 8, -

И 5А8, -И 589, - С(О)НА8, -ОЙ С(О)Н8, - (ОО, - С(О)8о, - ОС), - С(О)МАЯАА", - С(О) MAV, -

ГМ(Ая)», -МАЯАЯА, - MAT, -Г С(О)М(АУ)», -И5(О)2А8, -Й5(О)НЯ, - С(О)МАЗОН, -ИМАЗС(О) N, -

BY MASS, -I С(-М-ОВ8)А8, - С(-МН)-МНОВ8, -МНО(-МН)МН», -И 5(О0)2М(АУ)», -0И 5(О2М(ВУ )", -

MAUB(O)2гН8, -Г С(О)MARI MAU)», -GR(OKHO VV)», -ROR(OHOVNZ)», -GR(IOHOV' 9)" and -OYIG R(IFHOV' 9)" .

In certain variants of the embodiment of the compounds Formula (I), (I-A), (I-B) and (1)-(CHM), B" is selected from such as H,

C3-Salkyl, C3-Swcycloalkyl, and C3-Swheterocycloalkyl, and C:-Swalkyl, C3-Swcycloalkyl, and C3-

Svheterocycloalkyl groups are each optionally substituted with 1-3 BZ groups and each BZ is independently selected from such as: halogen, 0, C-Svhaloalkyl, I VU, I VU, ОЙ B and - OH.

In certain embodiments of the compounds of Formula (I), (I-A), (I-B) and (1)-(CHM), B" represents an aryl or heteroaryl group, optionally substituted by 1-3 B' From the groups and each KZ is independently chosen from the following: halogen, C-Svhaloalkyl, I KU, I VU, OSI Ve and - OH.

In certain embodiments of the compounds of Formulas (1), (I-A), (I-B) and (1)-(CHM), each Y is independently selected from such as: bond, -"O(CHg)t) -, Si-Svalkyl, Co-Svalkenylene, and Sgo-Svalkynylene, where each of such as: Si-Svalkyl, Co-Svalkenylene, and Co-Svalkynylene, the radical of Y is optionally substituted with 1-4 substituents independently selected from the following as: halogen, -H8, -OH8, -M(AZ)2, -P(IOHONB)", -OR(OHONB)", -P(OHOV'9)", and -OR(OHOHV'9)".

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (XM), (B

In the XX century

TO Se in their km

In M

MH,

Formula (XM).

In certain embodiments, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates), M-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, and mixtures of these isomers have the structure of Formula (XMI), A 7 VE K in their and l

E M

MH,

Formula (XMI).

In certain compounds, Formulas (XM) or (XMI), VE", BA and EZ are independently selected from the following: СООСНеCH 5, P, SI, Vi, -CHgОСН»z, CHgОСНеCH», -M(CHvz)», - (O(CHg)g)2OH, -O(CHg)24-OH, -O(CHg)2- a-(POzH»g), -O(CH2g)24-COOH, -O(CH2g)24-CH(CH3)", C2-Cv alkyl, substituted with 1-3 substituents, selected from such as: -OH , -CH3, cyclopropyl, -O(CH?g)2g-4-

СООН, -О(СНг)24(РозНГ), -СООН, СООСН», and -СООСНоСН:И. In some embodiments of such compounds, B" represents H. In certain of these compounds, the phenolic ring of the phenethyl group has from one to three E"Z groups. Optionally, B" represents H or -CH3. In certain embodiments, these compounds have two B" groups, and those KE" groups are selected from the group consisting of: -CH3, -CHneCH3, -CE3, -

CHhOH, -OSH», -СООСН», -chHOOSHSN with, E, SI, Vi, -CHhOsSnH», -CHhOSNegCH», -M(CH3)2g, -«(О(CH?g)g)2-OH, -

O(CHg)25A-OH, -O(CHg)2g-4-(POzNeg). -О(СНг)24-СООН, -О(СНг)2-4-СН(СН3)г, С2-Св alkyl substituted with 1-3 substituents selected from such as: -ОН, -СН3, cyclopropyl , -O(CHg)2-4-COOH, -

О(СНЗг)гА(РозНаг), -СООН, СООСН», and -СООСНеСН:».

In certain variants of the embodiment of the compounds of the Formula XIII, XIM, XM or XMI, the compound is selected from such as: 2-(4-(2-(5-amino-8-methylbenzo| 1, 7|naphthyridin-2-yl)ethyl)- 3-methylphenyl)propan-2-ol;. 2-(4-methoxy-2-methylphenethyl)-8-methyl-benzo| 1, 7UInaphthyridin-5-amine; 2-(2,4- dimethylphenethyl)benzo SHI 7|naphthyridin-5-amine; ethyl 4-(2-(5-amino-8-methyl-benzo|CP1, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 2-(4-(Dimethylamino)phenethyl)-8-methyl-benzoS/I1,7|Naphthyridin-5-amine, and 2-(4-methoxy-phenethyl)-8-methylbenzoSHI, 7|Naphthyridin-5-amine . Each of these compounds separately includes a preferred embodiment of the compounds, compositions, and methods disclosed herein.

In certain embodiments, a compound of Formula (I) as disclosed herein is combined with an antigen, and optionally a carrier, a pharmaceutically acceptable excipient or excipient, to form an immunogenic composition. In certain embodiments, the compounds of Formula (XMI) as disclosed herein are combined with an antigen, and optionally a carrier, a pharmaceutically acceptable excipient or excipient, to form an immunogenic composition. In other embodiments, such immunogenic compositions comprise a compound of Formula (II) and an antigen, wherein the antigen includes, but is not limited to, a bacterial antigen, a viral antigen, a fungal antigen, a tumor antigen, or an antigen associated with 5TO, Alzheimer's disease, respiratory disorders, autoimmune disorders such as, by way of example only, rheumatoid arthritis or lupus, pediatric disorders, and obesity, and wherein the amount of the compound is an amount effective to enhance an immune response to the antigen in a subject to whom the composition is administered. In other embodiments, such immunogenic compositions include a compound of Formula (XMI) and an antigen, wherein the antigen includes, but is not limited to, a bacterial antigen, a viral antigen, a fungal antigen, a tumor antigen, or an antigen associated with 5TO, Alzheimer's disease, disorders respiratory, autoimmune disorders such as, by way of example, rheumatoid arthritis or lupus, pediatric disorders, and obesity, and wherein the amount of the compound is an amount effective to enhance an immune response to the antigen in a subject to whom the composition is administered. Suitable antigens for use in such immunogenic compositions are disclosed herein.

In certain embodiments, such immunogenic compositions include a bacterial antigen strain

Meyvzegpia tepipoide5, such as serogroup A, C, M/135, M and/or B. Specific antigens for use in these compositions are disclosed herein. In other embodiments, such immunogenic compositions and others provided herein are used as vaccines; their use in the treatment of disorders associated with the antigen included in the composition is disclosed in this description.

In certain variants of the embodiment of the compounds Formulas (I), (I-A), (I-B) and (1)-(KHMI), each short circuit is independently selected from such as: GK, 1 ОВ, I 88, -Г ОВ, - I588, I BA, - (UN, - (VU), - C(O)M(VU)", -

И 5Б(О02Н88, -и 5(О)Н8, -И Р(ИОХОНВ)», -ОИ Р(IFHOVZ)», - Р(IFOHOV' 9)» and -ОЙ R(IFHOV' 9)».

In certain embodiments of the compounds of Formulas (1), (I-A), (I-B) and (1)-(HMI), each Y is independently selected from such as: bond, -"O(CHg)t) -, Si-Svalkyl, Co-Svalkenylene and Cg-Svalkynylene, where each of the groups, such as: Si-Svalkyl, Se-Svalkenylene and C2-Svalkynylene, of radical I. is optionally substituted with 1-4 substituents, which independently choose from such as: halogen, -H8, -OH8, -M(VU)2, -P(IOHONB)", -OR(OHOHNB)", -P(PHHOV9)", and -OR(OHHOV" 9)" .

In certain embodiments of the compounds of Formulas (1), (I-A), (I-B) and (1)-(HMI), B' and K2 each represent

N.

In certain embodiments of the compounds of Formula (1), (I-A), (I-B) and (1)-(HMI), BZ and E, when present, are independently selected from such as: H, halogen, Si-Svalkyl , Se-Swalken, Sgo-Swalkin and Si-Swalkoksi group.

In certain embodiments of the compounds of Formulas (I), (I-A), (I-B) and (1)-(HMI), B'"E represents aryl or heteroaryl, where aryl and heteroaryl groups are optionally substituted by with the help of 1-3 substituents selected from such as: halogen, -H8, -ONB, IB? and -M(AZU)". In other variants of the embodiment of compounds Formula (I), (I-A), (1- B) and (1)-(HMI), B'? represents phenyl, optionally substituted with 1-3 substituents selected from such as: halogen, -H8, -OH8, and -M(ВУ)» .

In certain embodiments of compounds Formula (I), (I-A), (I-B) and (1)-(XI), AB? choose from such as: H,

C-Svalkyl and C-Svhaloalkyl.

In certain embodiments, the compound of Formula (I) is as follows: 3-chloro-2-methylbenzo Х1,7|Inaphthyridin-5-amine; 2-methylbenzo DY, 7|Inaphthyridin-5-amine; pyrimido|4,5-c)quinolin-5-amine; 2-(ethoxymethyl)benzo CI, 7|Inaphthyridin-5-amine; pyrimido|4,5-c)quinoline-3,5-diamine; 3-(methylthio)pyrimido|4,5-c)quinolin-5-amine; (E)-2-(2-cyclopropylvinyl)/benzo DI, 7|naphthyridin-5-amine; (E)-2-(pent-1-enyl)benzo|CI1, UInaphthyridin-5-amine; 4-(5-aminobenzo[C1,7]Inaphthyridin-2-yl)-2-methylbut-3-yn-2-ol; 2-pentylbenzo (1,7|naphthyridin-5-amine; (E)-2-(prop-1-enyl)benzo H(1,7|naphthyridin-5-amine; (E)-2- (Z-phenylprop -1-enyl/benzo CY, 7|naphthyridin-5-amine; / 2-(2-cyclopropylethyl)benzo CY, 7Naphthyridin-5-amine; 4-(5-aminobenzo|(CH1,7|naphthyridin-2-yl )-2-methylbutan-2-ol; 2-propylbenzo|(ХІ1, ХInaphthyridin-5-amine; 2-(3-phenylpropyl)/benzo|ХІ1, ХInaphthyridin-5-amine; 2-ethylbenzo ХІ, 7Inaphthyridin-5- amine; 2-(2-methylprop-1-enyl)benzo|DY,7|naphthyridin-5-amine; /2-isobutyl-benzo(ЦЙ1,7|Inaphthyridin-5-amine; ,4-difluorostyryl)benzo|C1, Y-naphthyridin-5-amine; /(E)-2-(hex-1-enyl)/benzo DI, 7|naphthyridin-5-amine;

(E)-2-(2-cyclohexylvinyl)-benzo DY, 7-Inaphthyridin-5-amine; Е)-2-(3- (trifluoromethyl)styryl)benzo|CI1, YInaphthyridin-5-amine; (E)-2-(3-Methoxystyryl)benzo DP, 7|Inaphthyridin-5-amine; 8-methyl-2-vinylbenzo|ЦИ1,7|naphthyridin-5-amine; (E)-8-methyl-2-styrylbenzo| DY, 7-Inaphthyridin-5-amine; 2-(2-cyclohexylethyl)benzo|D/I1,7UInaphthyridin-5-amine; 2-fluorobenzo| SHI, 7UInaphthyridin-5-amine; /2-(3-"trifluoromethyl)phenethyl)benzo|D1,7|naphthyridin-5-amine; 2-(2,4-difluoro-phenethyl)benzo DI, 7|naphthyridin-5-amine; 2-(З -methoxyphenethyl)benzo DP, 7|Inaphthyridine-

B-amine; 2-hexylbenzoshrY, 7|Inaphthyridin-5-amine; 2-ethyl-8-methylbenzo|DC(1,7|naphthyridin-5-amine; 8-methylbenzo H/1,7|Inaphthyridin-5-amine; 8-methyl-2-phenethylbenzo| 1,7UInaphthyridin-5-amine ; methyl 5-aminobenzo| 11, 7YInaphtiridine-3-carboxylate; 5-amino-M-methylbenzo| DY, 7| Inaphthyridine-3-carboxamide; (5-aminobenzo| DY, 7| naphthyridin-3-yl)methanol; 8 -phenylbenzo DI, 7|naphthyridin-5-amine; 3- (ethoxymethyl)-benzo| 1,7UInaphthyridin-5-amine; benzoSHI,7|naphthyridine-3,5-diamine; benzo DP, 7UInaphthyridin-5-amine; methyl 5-aminobenzosHI, 7|naphthyridine-8-carboxylate; 5-aminobenzo| DY, 7|naphthyridine-8-carboxylic acid; ethyl 5-aminobenzo|(DY1,7|naphthyridine-8-carboxylate; (5-aminobenzo ХІ, 7 |naphthyridin-8-yl)methanol; 5-amino-benzo| DY, 7|naphthyridine-3-carboxylic acid; 5-aminobenzo DY, 7|naphthyridin-3-carbaldehyde; 2-(0- tolyethynyl)/benzo|SHI1 ,7|naphthyridin-5-amine; / 2-(m-tolylethynyl)/benzoSHI,7|Inaphthyridin-5-amine; /- 2-(p-tolylethynyl/benzo DI,7|naphthyridin-5-amine;. 2 -(2-Methylphenethyl)benzo CY, 7|Naphthyridin-5-amine; 2-(3-Methylphenethyl)-benzoxyl,7|Naphthyridin-5-amine; 2-(4 -methylphenethyl)benzo SHII, 7|Inaphthyridin-5-amine; 3- chloro-2-(ethoxymethyl)benzo|(DC(I1,7|naphthyridin-5-amine; pyrazine|2,3-c|quinolin-5-amine; 9- chlorobenzo SHI, 7|Inaphthyridin-5-amine ; 8-chlorobenzo DI, 7-Naphthyridin-5-amine; 9- methylbenzo SHI, 7|Naphthyridin-5-amine; 10-methylbenzo DP, 7-Naphthyridin-5-amine; ethyl 5-aminobenzo|CI, 7-Naphthyridin-9-carboxylate; 5 -aminobenzo| DY, 7| Inaphthyridin-9-carboxylic acid; 8- methoxybenzo| DY, 7| naphthyridin-5-amine; 7-fluorobenzo| 1, 7Inaphthyridin-5-amine; 8- (methylsulfonyl) benzo| DY1,7 |naphthyridin-5-amine; 8-(trifluoromethyl)-benzo DY, 7-naphthyridin-5-amine; 8-fluorobenzo SHI, 7/|Inaphthyridin-5-amine; 3-methoxybenzo|DC(І1,7|naphthyridin-5- amine; 3-butoxybenzo|C1, YInaphthyridin-5-amine; 3-(benzyloxy)benzo|DY, 7UInaphthyridin-5-amine; 3-methylbenzo ХІ, 7|Inaphthyridin-5-amine; 3-chlorobenzo ХІ, 7Inaphthyridin-5-amine -amine; MZ,MZ- dimethylbenzo DI, 7|Inaphthyridin-3,5-diamine; MZ-butylbenzo| CI, 7|naphthyridine-3,5-diamine; 3-vinylbenzo DP, 7Inaphthyridin-5-amine; Z-ethylbenzo | CI, 7|Naphthyridin-5-amine; 3-fluorobenzo SHI, 7/|Naphthyridin-5-amine; 2-(trifluoromethyl )benzo|D(I1, 7UInaphthyridin-5-amine; 2- methoxybenzo| DY, 7|naphthyridine-5-amine; 2-(benzyloxy)benzo SH, 7|Inaphthyridin-5-amine; 2-vinylbenzo DP, 7Inaphthyridin-5-amine; 2-phenylbenzo| DI, YInaphthyridin-5-amine; (E)-2- styrylbenzo|ЦІ1, 7ІNaphthyridin-5-amine; 2-phenethylbenzo DY, 7|naphthyridin-5-amine; (E)-2-(3-Methoxyprop-1-enyl)-benzo DY, 7|Inaphthyridin-5-amine; 2-(3-methoxypropyl)benzo CH, 7|Inaphthyridin-5-amine; 2-(prop-1-en-2-yl/benzoShP, 7|Inaphthyridin-5-amine; 2-isopropylbenzo| 1,7YInaphthyridin-5-amine; 1- methylbenzo Х/1,7|Inaphthyridin-5-amine; benzo|c|P1,b|Naphthyridin-6b-amine; pyridoY3,2-CH,7U|naphthyridin-6-amine; thieno(2,3-c|quinolin-4-amine; 8-methyl-2-(naphthalene -2-ylethynyl)-benzoSHI,7|naphthyridin-o-amine; 8-methyl-2-(2-(naphthalen-1-yl/ethyl)benzo|DI, 7|naphthyridin-5-amine; 8-methyl- 2-(2-(Naphthalin-2-yl)/'ethyl)ubenzoSTP, 7|Inaphthyridin-5-amine; 8-methyl-2-(naphthalin-1-ylethynyl)benzo|(1,7UInaphthyridin-5-amine; /4-(2-(5-amino-8-methylbenzo|Ш/1,7|naphthyridin-2-yl)ethyl)benzoic acid; /3-(2-(5-amino-8-methylbenzo) |Inaphthyridin-2-yl)ethyl)benzoic acid; 2-(z-chlorophenethyl)-8-methylbenzo H/1,7|Inaphthyridin-5-amine; 2-(2-chlorophenethyl)-8-methylbenzo DP, 7| Inaphthyridin-5-amine; (3-(2- (5-amino-8-methylbenzo|DI, 7|Inaphthyridin-2-yl)ethylphenyl)methanol; 2-(4-chlorophenethyl)-8- methylbenzo Х/1, 7|Naphthyridin-5-amine; 8-(trifluoromethyluphenanthridin-6b-amine; benzois)(2,7|naphthyridine-

B-amine; 2-(trifluoromethyl)benzo|DI1, YInaphthyridin-5-amine; 2-tert-butoxybenzo|(DY1,7|naphthyridin-5-amine; 5-aminobenzo DY, 7|naphthyridin-2-ol; 2-((4-butylphenyl)ethynyl)ubenzo CHY, 7|naphthyridin-5-amine ; 2-(4-butylphenethyl)-benzo DP, 7|Inaphthyridin-5-amine; 1-benzyl-5-chloro-7-(trifluoromethyl)-1,2- dihydropyrido|3,4-b|Ipyrazine-Z( 4H)-one; 2-(2-(6-Methoxynaphthalen-2-yl/ethylubenzo DY, 7Inaphthyridin-5-amine; 2-(4-butylphenethyl)-8-methylbenzo CY, 7Inaphthyridin-5-amine; 2-( 4-propylphenethyl)-benzo DP, 7|Inaphthyridin-5-amine; 2-(4--trifluoromethyl)phenethyl)benzo|ЦІ1,7|Inaphthyridin-5-amine; 2-(2,5- dimethylphenethyl)-8- methylbenzo SH, 7Inaphthyridin-5-amine; 8-methyl-2-(4-propylphenethyl)benzo|C1, 7UInaphthyridin-5-amine; 8-methyl-2-(2,4,5-trimethylphenethyl)-benzo DP, 7UInaphthyridine -5-amine; 2-(2,5-dimethylphenethyl)benzo CI, 7|Naphthyridin-5-amine; 2-(4- isopropylphenethyl)-8-methylbenzo CHY, 7|Naphthyridin-5-amine; 2-(4 -heptylphenethyl)-8-methylbenzo ХІ, 7|Inaphthyridin-5-amine; 2-(4-isobutoxyphenethyl)-8-methylbenzo|ЦІ1, 7ІInaphthyridin-5-a mine; 2-(4-(2-methoxyethoxy)methoxy)phenethyl)-8-methylbenzo| 1, 7UInaphthyridin-5-amine; 8-methyl-2-(4-(2- phenoxyethoxy)phenethyl)benzo SHI, 7|Inaphthyridin-5-amine; 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)phenethyl)-8-methylbenzo| DY, 7|naphthyridine-5-amine; 2-(4-butoxy-2-methylphenethyl)-N-butyl-8-methylbenzo|(DC(1,7|naphthyridin-5-amine; 8-methyl-2-(4-(4-phenylbutoxy)phenethyl)benzo |Ц1, 7|Inaphthyridin-5-amine; 2-(4-(allyloxy)phenethyl)-8-methylbenzo SHІ, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(3-phenylpropoxy)phenethyl) )-

benzo DP, 7UInaphthyridin-5-amine; 2-(4-(heptan-4-yloxy)phenethyl)-8-methyl-benzo|(І1,7|naphthyridin-5-amine; 8-methyl-2-(4-(4-methylpent-3-enyloxy) uphenethyl)-benzo|/1,7|naphthyridin-5-amine; 2-(4-(2-cyclohexylethoxy)phenethyl)-8-methyl-benzo| DI, 7|inaphthyridin-5-amine; 2-(4- isopropoxyphenethyl)-8-methyl-benzo|DI1,7|naphthyridin-5-amine; 2-(4-(3,3-dimethylbutoxy)phenethyl)-8-methyl-benzo DP, 7UInaphthyridin-5-amine; 2-( 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2-methylphenethyl)-8- methylbenzo SH, 7|Inaphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(4-(dimethylamino)phenethyl)benzo Ch(1,7|naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(2,4-dimethylphenethyl)benzo CH, 7|naphthyridin-5-amine; diethyl 3-(2-(4-( 2-(2-Hydroxyethoxy)ethoxy)-2-methylphenethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-ylamino)propyl-phosphonate; (E)-M-(4-(2-(5- aminobenzo| CI) . 5-aminobenzo|DY1,7|naphthyridin-2-yl)ethyl)phenyl)acetamide; M-(4-(2-(5-amino-8-methylbenzo DY, 7|naphthyrides) n-2-yl)ethyl)phenyl)-4-methylbenzenesulfonamide; 3-methyl-9-p-tolyl-9,10-dihydrobenzoHPfuroi(2,3-811,7|naphthyridin-6-amine; 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl )ethyl)-3-methylbenzonitrile; 4-(2-(5-amino-8-methylbenzo DC, 7|Inaphthyridin-2-yl)ethyl)-M-(2-aminoethyl)-3-methylbenzamide; /- 2- (4-(2-(5-amino-33-chloro-8-methylbenzo)/1,7|inaphthyridin-2-yl)ethyl)-3-methylbenzamido)acetic acid; /(5)-2-(4- (2-(5-amino-3-chloro-8-methylbenzo|C1,7UInaphthyridin-2-yl)ethyl)-3-methylbenzamido)-4-methylpentanoic acid; 4-(2-(5-amino-3-chloro -8-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide; 8-methyl-2-(2-methyl-4-(1H- Tetrazol-5-ylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; methyl 2-(4-(2-(5-amino-8-methyl-benzo DP, 7|Inaphthyridin-2-yl)ethyl)-3 -methylbenzamido)-4-methylpentanoate; methyl 2-(4-(2-(5-amino-8-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamido)acetate; 2-(4-( 2-(5-amino-8-methylbenzo DP, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamido)-4-methylpentanoic acid; 2-(4-(2-(5-amino-8-methylbenzo DI) , 7Inaphthyridin-2-yl)eth yl)-3-methylbenzamido)-acetic acid; 6-(5-amino-3-methylbenzo(/1,7|Inaphthyridin-2-yl)hexan-1-ol; 7-(5-amino-8-methylbenzo|CP1,7Inaphthyridin-2-yl)heptanoic acid ; 11-(5-amino-8-methylbenzo H/1,7|Inaphthyridin-2-yl)undecan-1-ol; 2-phenethylbenzo C, 7Inaphthyridin-5-amine; ethyl 2-(4- (2-( 5-amino-8-methylbenzo|DP, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)acetate; 2-(4-(2-(5-amino-8-methylbenzo) TSI1,7|Inaphthyridin-2 -yl)ethyl)-3-methylphenoxy)acetic acid; 3-(4-(2-(5-amino-8-methylbenzo 1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propanoic acid; 6 -(4-(2-(5-amino-8-methylbenzo)/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)-caproic acid; 8-methyl-2-(2-methyl-4 - (methylthio)phenethyl)benzo DP, 7|Inaphthyridin-5-amine; 8-methyl-2-(4- (methylsulfonyl)/phenethyl)benzo| DY, 7|Inaphthyridin-5-amine; 2-(4-( hexyloxy)-phenethyl)-8- methylbenzo SHI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-phenethoxyphenethyl)-benzo|ЦІ1, 7Inaphthyridin-5-amine; 2-(4-cyclobutoxyphenethyl)-8 -methylbenzo CI, 7-Naphthyridin-5-amine; 8-methyl-2-(4- (pentyloxy)phenethyl)benzo| DI, 7|naphthyridine-5 -amine; 8-methyl-2-(4-(4-methylpentyloxy)phenethyl)benzo|C1, 7-Naphthyridin-5-amine; 8-bromo-3-methoxy-benzo

B-amine; 2-(tert-butyldimethylsilyl)ethynyl)-benzoyl, 7N|naphthyridine-5-amine; 2-(2-fluorophenyl)ethynyl)benzo CH, 7|Inaphthyridin-5-amine; 2-((3-fluorophenyl)ethynyl)ubenzo OR, 7|naphthyridin-5-amine; 2-(4-fluorophenyl)ethynyl)-benzo(ЦІ1,7|naphthyridin-5-amine; 2-(thiophen-3-ylethynyl)ubenzo ЧІ, 7|Inaphthyridin-5-amine; 2-ethynylbenzo Ч(1, 7 |Inaphthyridin-5-amine; 2-(2-fluorophenethyl)benzo|ЦІ1, 7ІInaphthyridin-5-amine; 2-(3-fluorophenethyl)benzo CH, 7|naphthyridin-5-amine; 2-(4-fluorophenethyl)- benzoSHI,7|naphthyridine-o-amine; /2-(2-(thiophen-3-yl/ethyl/benzo|DI1,7|naphthyridine-5-amine; ethyl 5-aminobenzo DP, 7U|Inaphthyridine-2-carboxylate ; ethyl 5-amino-8-methylbenzo|(DI1,7|naphthyridine-2-carboxylate; (5-aminobenzo|ЦІ1,7UInaphthyridin-2-yl)umethanol; 2-(3,4- dimethylphenethyl)benzo ХЙ 7|naphthyridine -5-amine; 1-chloro-8-methylbenzo(CI1,7|naphthyridin-5-amine; 8-methyl-1-(3-phenylpropyl/benzo CH, 7Y|naphthyridin-5-amine; (2)-2 -(2-(benzo|(4|I11,3)dioxol-5-yl)vinyl)-8-methylbenzo SHI, 7|Inaphthyridin-5-amine; (2)-2-(4-methoxy-2-methylstyryl )-8-methylbenzo SHI, 7|Inaphthyridin-5-amine; 2-(3,4-dimethyl-phenethyl)-8-methylbenzo TSI, 7Inaphthyridin-5-amine; 2-(3,5-dimethylphenethyl)-8- methyl-benzo|(ЦІ1,7|naphthyridin-5-amine; 8-methyl-2-(1-phenylvinyl)ubenzo DP, 7Inaphthyridin- 5-amine; 8-methyl-2-(4-phenylbutyl)benzo CH, 7|Inaphthyridin-5-amine; 8-methyl-2-(1-phenylethyl)-benzo(I1,7|naphthyridin-5-amine; 2-(2-(benzofuran-5-yl)ethyl)-8-methyl-benzoSHP, 7U|Inaphthyridin-o -amine; // (27)-2-(2-ethoxyvinyl)-3-methylbenzo(PSHI1,7|naphthyridine-5-amine; /-2-(2-ethoxyethyl)-8-methylbenzo|ЦІ1,7Іnaphthyridine-5 -amine; 2-(chloromethyl)-8-methylbenzo|ЦІ1, 7UInaphthyridin-5-amine; 8-methyl-2-(2-nitroethyl)benzo ЧІ, 7|Inaphthyridin-5-amine; diethyl 2-(5- amino-8-methylbenzol, 7naphthyridin-2-yl)methyl)malonate; 2-(isopropylsulfonyl)-8-methylbenzol/1,7|inaphthyridin-5-amine; 2-(methoxymethoxy)methyl)-8-methylbenzol , 7|naphthyridine-5-amine; 8-methyl-2-(methylamino)methyl)-benzo OR, 7|Inaphthyridin-5-amine; tert-butyl 5-amino-8-methylbenzo CHY, 7|Inaphthyridin-2-ylcarbamate; 8-methyl-2-(phenylamino)methyl)benzo SH, 7-Naphthyridin-5-amine; 2-(aminomethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine; 8-methyl-2-(pyrrolidin-1-ylmethyl)-benzo DP, 7-Naphthyridin-5-amine; Me--(2,4-dimethoxybenzyl)-8-methylbenzo CY, 7/|Inaphthyridine-2,5-diamine;

Me,M2,b-trimethylbenzo D1, 7Inaphthyridine-2,5-diamine; M2,8-dimethylbenzo| SHI, 7Uinanaphthyridine-2,5-diamine; 8-methyl-2-(pyrrolidin-1-yl)ubenzo DP, 7|Inaphthyridin-5-amine; 2-(5-amino-8-methylbenzo|DI, 7|Inaphthyridine-

2-yl)-1-phenylethanol; 2-(2-aminoethyl)-8-methylbenzo|D(1,7|naphthyridin-5-amine; 2-hydrazinyl-8- methylbenzo H/1,7|Inaphthyridin-5-amine;. 1-(5-amino -8H-methylbenzo(CH, 7|naphthyridin-2-yl)-2-methylpropan-2-ol; 2-(5-amino-H-methylbenzo CH, 7|naphthyridin-2-yl)-1-(4 -Methoxyphenyl)-ethanol; 2-(biphenyl-2-yl)-8- methylbenzo SHI, 7|Inaphthyridin-5-amine; 2-(2-(2,6-dimethylpyridin-3-yl)ethyl)-8- methylbenzo SHI, 7|Inaphthyridin-5-amine; 2-(2-(5-methoxypyridin-2-yl)ethyl)-8- methylbenzo SHI, 7|Inaphthyridin-5-amine; 3-(4-(2-( 5-amino-8-methylbenzo|CI,7-naphthyridin-2-yl)ethyl)phenyl)propanoic acid; 5-(2-(5-amino-8-methylbenzo|1,7-Naphthyridin-2-yl)ethyl)-4- methylpyridin-2(1H)-one; 6-(2-(5-amino-8-methylbenzol, 7|Naphthyridin-2-yl)ethyl)pyridin-3-ol; 3-methyldibenzo|, CI, 7Lnaphthyridin-6 -amine; 8-methyl-2-(4-«"«trifluoromethoxy)-phenethyl)benzo|D(1,7|naphthyridin-5-amine; 2-(2-(2,3-dihydro-1H-inden- 5-yl)ethyl)-8-methylbenzo H/1,7|Inaphthyridin-5-amine; 2-(2-(2,3-dihydro-1H-inden-5-yl)ethyl)-benzoI, 7Lnaphthyridine- 5- amine; (E)-3-(4-(2-(5-amino-d-methylbenzo OR, 7|naf) tyridin-2-yl)ethyl)-3-methylphenyl)acrylic acid; (E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo C1,7|Inaphthyridin-8-yl)acrylate; MU, M5-dibutyl-benzo| CI, 7|naphthyridine-3,5-diamine; 8-(prop-1-en-2-yl/ubenzo DY, 7-Naphthyridin-5-amine; 5-aminobenzo| 11, 7U-Naphthyridin-8-carbonitrile; (E)-8-(3-methylbut-1-enyl)- benzo|CI, Yanftyridin-5-amine; 8-(2-methylprop-1-enyl)/benzo|(DI1,7|naphthyridin-5-amine; (E)-8-(pent-1-enyl/ubenzo| DY1, 7|naphthyridin-5-amine; (E)-8-styryl-benzo DY, 7UInaphthyridin-5-amine; (E)-8-(2-cyclopropylvinyl)-2-phenethylbenzo|C1, 7UInaphthyridin-5-amine ; 8-pentyl-benzo DI, 7|naphthyridin-5-amine; (E)-8-(2- cyclopropylvinyl)/benzo| (1, 7UInaphthyridin-5-amine; 8-(2-cyclopropylethyl)-2- phenethylbenzo |C1, 7UInaphthyridin-5-amine; pyridoI1,2-C|1, Inaphthyridine-b-amine; 9-phenethylpyrido|1,2-cI1,7Inaphthyridin-b-amine; methyl 5-amino-2-(4-methoxy -phenethyl)-benzoSHI, 7|Naphthyridine-8- carboxylate; 8-nitrobenzoSHI,7|naphthyridine-5-amine; 3-chloro-8-methylbenzo( DI, 7|naphthyridine-5-amine; methyl 5-amino-3 -chlorobenzo|ЦІ1, 7ІInaphthyridine-8-carboxylate; methyl 5-amino-3-fluorobenzo ХІ, 7|Inaphthyridine-8-carboxylate; З-chloro-8-nitrobenzo| DY, 7|Inaphthyridin-5-amine; (5- amino-3-chlorobenzol/1,7|inaphthyridin-8-yl)methano l; (5-amino-2-phenethyl-benzo[CI1,7]Inaphthyridin-8-yl)umethanol; 4-(2-(5-amino-8-fluoro-benzoSHI, 7|naphthyridin-2-yl)ethyl)benzaldehyde; 2-(4-(2-(5-amino-8-fluorobenzoic acid, 7|Inaphthyridin-2-yl)ethyl)-benzylamino)ethanol; 3-(4-(2-(5-amino-8-fluorobenzoic acid, 7-inaphthyridin-2-yl)ethyl)-benzylamino)propan-1-ol; 8-fluoro-2-(4-(2- methoxyethylamino)methyl)-phenethyl)-benzo CH, 7-Naphthyridin-5-amine; 8-(tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenethyl)benzo|CI1, N-naphthyridin-5-amine; (5-amino-2-(4-methoxy-2-methylphenethyl)-benzoH(D(1,7|naphthyridin-8-yl)methanol; 3-(2-(5-aminobenzo| 411,7UInaphthyridin-2-yl) )uethylphenol; 2-(2-methoxyphenethyl)-benzo| DI, 7|naphthyridin-5-amine; 2-(4-ethylphenethyl)-benzo| 1, 7)|inaphthyridin-5-amine; 2-(4-ethylphenethyl )-8- methylbenzo Х/1,7|Inaphthyridin-5-amine; 2-(4-(dimethylamino)phenethyl)-benzoХХ, 7|Inaphthyridin-5-amine; 2-(4-(piperidin-1-ylphenethyl) benzo CH, 7|naphthyridin-5-amine; 2-(4-tert-butylphenethyl)-8-methyl- benzo DP, 7U-naphthyridin-5-amine; 8-methyl-2-(4-(piperidin-1-ylphenethyl) -benzo|ЦІ1, YInaphthyridin-5-amine; 2-(4-Methoxyphenethyl)-8-methylbenzo|ЦІ1, Yanftyridin-5-amine; 2-(3,5-dimethoxyphenethyl)-8-methyl-benzo DP, 7UInaphthyridin- 5-amine; 8-methyl-2-(2-(trifluoromethyl)phenethyl)-benzo|CI1, YInaphthyridin-5-amine; 8-methyl-2-(2-(1-methyl-1H-imidazol-5-yl) )uethyl)-benzo Schi, 7|naphthyridin-5-amine; 4-(2-(5-amino-8- methylbenzo Schi, 7|Inaphthyridin-2-yl)ethyl)-M-hydroxybenzimidamide; 4-(2- (5-amino-8-methylbenzol,7|inaphthyridin-2-yl)ethyl)benzonitrile; 8-methyl-2-(4-(1-morpholinoeth yl)phenethyl)benzo C(1,7|Inaphthyridin-5-amine; 2-(4-aminophenethyl)-8- methylbenzo SH, 7|Inaphthyridin-5-amine; 1-(4-(2-(5-amino-8-methylbenzo|1, 7-Naphthyridin-2-yl)/ethyl)phenyl)guanidine; 8-methyl-2-(4-(1-(phenethylamino)ethyl)/phenethyl)-benzogPCI1,7|naphthyridin-5-amine; 2-(4-(2-(5-amino-8-methylbenzo|SHI, 7|naphthyridin-2-yl)ethyl)phenyl)acetonitrile; 2-(4-(piperidin-1-ylmethyl)phenethyl)benzo OR 7|naphthyridin-5-amine; 1-(4-(2-(5-aminobenzoic acid, 7|naphthyridin-2-yl)ethyl)benzyl)piperidin-4-ol; 2-(4-(aminomethyluphenethyl)benzo|ЦІ1, 7|Inaphthyridin-5-amine; 2-(4- ((ethylamino)methyl)phenethyl)benzo|ЦІ1, 7ІInaphthyridin-5-amine; 2-(4-(2 -aminopropan-2-ylphenethyl)benzo|DI, 7|naphthyridin-5-amine; 1-(1-(4-(2-(5-aminobenzo ЧИ, 7|Inaphthyridin-2-yl)/ethyluphenyl)ethyl)pyrrolidine -3-carboxylic acid; 8-methyl-2-(4-(1-(phenylamino)-ethylufenethyl)benzo 1, 7|Inaphthyridin-5-amine; 2-ethyl-8-methyl-benzoSHI, 7|Inaphthyridin-5 -amine; /(5-amino-8-methylbenzo CH, 7|Inaphthyridin-2-yl)umethanol; 8-methyl-2-propylbenzo| 1, 7|naphthyridin-5-amine; 2-(2-(1H- Indole-5-yl)ethyl)-8-methyl-benzo DP, 7|Inaphthyridin-5-amine; 2-(4-ethoxyphenethyl)-8- methylbenzo ХІ1,7|Inaphthyridin-5-amine; 8-methyl-2 -(4-phenoxyphenethyl)benzo CH, 7|naphthyridin-5-amine; 2-(2,4-dimethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; 2-(2,4-dimethylphenethyl)-8-methyl - benzo SHI, 7Naphthyridin-5-amine; 2-(4-methoxy-2-methylphenethyl)-8-methyl-benzo| DI, 7|naphthyridin-5-amine; 4-(2-(5-amino-8- methylbenzo (1,7Inaphthyridin-2-yl)ethyl)-3-methylphenol; 2-(2-(2,3- dihydrobenzofuran-5-yl)ethyl)-8-methylbe nzo DP, 7|Inaphthyridin-5-amine; 2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethanol; 3-methyl-9-phenyl-9,10-dihydrobenzo|Pfuro|2,3-

BI, 7|Inaphthyridin-6-amine; 8-methylbenzo DI, 7|naphthyridine-2,5-diamine; 1-(5-amino-8-methylbenzo-1,7-inaphthyridin-2-yl)upropan-2-ol; 2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)acetonitrile; M-(5-amino-8-methyl-benzo|CI1, 7-Inaphthyridin-2-yl)lacetamide; 2-(5-amino-8-

methylbenzo (CII1,7|Inaphthyridin-2-yl)-1-(2,4-dimethylphenyl)ethanol; 2-(2-(6-methoxy-4-methylpyridin-3-yl)ethyl)-8-methylbenzo| DY, 7-Inaphthyridin-5-amine; 4-(4-(2-(5-amino-β8-methylbenzo DP, 7|Inaphthyridin-2-yl)/ethyl)phenyl)butan-1-ol; methyl 3-(4-(2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)/ethyluphenyl)upropanoate; 3-(4-(2-(5-amino-1-methylbenzo|DY) , 7|Naphthyridin-2-yl)ethyl)phenyl)propan-1-ol; 4-(4-(2-(5-amino-1-methylbenzol) -2-ol; 2-(4-(aminomethyl)phenethyl)-8-methyl-benzo DI, 7|naphthyridin-5-amine; (E)-ethyl 3-(4-(2-(5-amino-8 - methylbenzo ХІ/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate; ethyl 3-(4-(2-(5-amino-8- methylbenzo ЦІ1,7|Inaphthyridin-2-yl) ethyl)-3-methylphenyl)propanoate; 2-(4-(2-(5-amino-8-methylbenzo C1,7|inaphthyridin-2-yl)ethyl)-3-methylbenzyl)propane-1,3-diol; 3-(4-(2-(5-amino-8-methylbenzol/1,7|inaphthyridin-2-yl)ethyl)-3-methylphenylpropanoic acid; 5-amino-2-(4-methoxy-2-methylphenethyl) )-benzoschi,7|naphthyridin-8-carbaldehyde; ethyl 4-(2-(5-amino-8-methyl-benzoschi, 7|naphthyridin-2-yl)ethyl)benzoate; 8-methyl-2-(4- methylphenethyl)-benzo|PC(І1,7|naphthyridin-5-amine; /2-(4-(2-(5-amino-Я-methylbenzo CH, 7|naphthyridin-2-yl)ethyl)phenyl)propan- 2-ol; (4-(2-(5-amino-8- methylbenzo ЦІ1,7|Inaphthyrs dyn-2-yl)ethylphenyl)methanol; ethyl 4-(2-(5-amino-8-methylbenzoic acid, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 4-(2-(5-amino-8-methylbenzo H1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoic acid; (4-(2-(5-amino-8-methylbenzo 1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)methanol; 8-methyl-2-(2,4,6- trimethylphenethyl) benzo CHY, 7|naphthyridin-5-amine;. 2-(4-(2-(5-amino-8-methyl-benzo (1,7 |naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol; 8-methyl-2-(4 -propoxyphenethyl)benzo DI, 7|naphthyridin-5-amine; (E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo DP, 7|Inaphthyridin-8-yl)acrylate; (E)-3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|C1,7YInaphthyridin-8-yl acrylic acid; ethyl 3-(5-amino-2-(4-methoxy-2- methylphenethyl)benzo|C1,7|Inaphthyridin-8-yl)/propanoate; 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|D(I1,7Inaphthyridin-8-yl)/propanoic acid; 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|D(I1,7Inaphthyridin-8-yl)propan-1-ol; (5-amino-benzo Х1,7|Inaphthyridin-8- ilumethanol; 5-aminobenzo|(DI1,7|naphthyridin-8-ol; 5-aminobenzo CH, 7|naphthyridine-8-carbaldehyde; 1-(5-aminobenzo| CH, 7UInaphthyridin-8-yl)ethanol; 1-( 5-aminobenzo|(DI1,7|naphthyridin-b8-yl)ethanone; 8-isopropyl-benzo DP, 7UInaphthyridin-5-amine; 8-vinylbenzo|D(1,7|naphthyridin-5-amine; 8-ethyl- benzo DP, 7|Inaphthyridine-

B-amine; 8-(Methoxymethyl)benzo|(DI1,7|naphthyridin-5-amine; (5-amino-2-phenethylbenzo|D/1,7|naphthyridin-8-yl)methanol; (5-amino-2-( 4-Methoxyphenethyl)-benzo|CI1, 7-Naphthyridin-8-yl)methanol; benzo IP, 7-Naphthyridin-5,8-diamine; 8-(aminomethyl)benzo|DY, 7|naphthyridin-5-amine; Z-fluoro-8 - methylbenzo SHI, 7|Inaphthyridin-5-amine; (5-amino-3-fluorobenzo| DI, 7|naphthyridin-8-yl)methanol; 3-chlorobenzo SHI, 7|Inaphthyridine-5,8-diamine; З- fluorobenzo|Ц1, 7UInaphthyridin-5,8-diamine; 8- isobutylbenzo DP, 7Inaphthyridin-5-amine; (E)-8-(prop-1-enyl/ubenzo|(ДЙ1,7|naphthyridin-5-amine; 8 - propylbenzoschi, 7U|Naphthyridin-5-amine; 8-(2-cyclopropylethyl)benzo CH, 7|Naphthyridin-5-amine; 8-phenethyl-benzo|DY, 7Y|naphthyridin-5-amine; (5-amino- 2-(4-bromophenethyl)benzo|DY, 7|naphthyridin-8-ylylmethanol; 2-(4-methoxy-2-methylphenethyl)-8-pentylbenzo CI, 7-naphthyridin-5-amine; 8-(2-cyclopropylethyl)- 2-(4-Methoxy-2-methylphenethyl)benzo|C1, 7-Inaphthyridin-5-amine; (5-amino-2-(4-propoxy-phenethyl)benzo DI, 7|naphthyridin-8-yl)methanol; (2-(2-(1H-indol-5-yl)ethyl)-5-amino-benzo DP, 7-Naphthyridin-8-yl)methanol; M-(4-(2-(5-amino-8-methylbenzo|ЦІ1, 7UInaphthyridin-2-yl)ethyl)phenyl)acetamide; methyl 4-(2-(5-amino-8-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 4-(2-(5-amino-8α-methylbenzo CP, 7Inaphthyridin-2-yl)ethyl)-M, 3-dimethylbenzamide; M-(2-acetamidoethyl)-4-(2-(5-amino-8-methylbenzo|DI, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamide; 4-(2-(5-amino-8-methylbenzo-CH1, 7|Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide; 2-(4-methoxyphenethyl)benzo DY, 7|naphthyridin-5-amine; 2-(4-Methoxy-2-methylphenethyl)benzo|D/I1, 7-Naphthyridin-5-amine; 4-(2-(5-amino-8-methyl-benzo|DI1,7|naphthyridin-2-yl)ethyl)-3-methylbenzamide; 4-(2-(5-amino-8-methyl-benzo DY, 7-Naphthyridin-2-yl)ethyl)-M, M,3-trimethylbenzamide; 4-(2-(5-amino-8-methyl-benzo DP, 7|Inaphthyridin-2-yl)ethyl)-M-(2-hydroxyethyl)-3-methylbenzamide; 4-(2-(5-amino-8-methylbenzo[D/I1,7-Naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-3-methylbenzamide; (4-(2-(5-amino-8-methylbenzo|D/I1, 7-Naphthyridin-2-yl)ethyl)-3-methylphenyl)-(pyrrolidin-1-yl)umethanone; 4-(2-(5-amino-8-methylbenzo (1,7 |naphthyridin-2-yl)ethyl)-M-(2-(diethylamino)ethyl)-3-methylbenzamide; (4-(2-(5 -amino-8-methylbenzo 1, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazin-1-yl)umethanone; (4-(2-(5-amino-β8-methylbenzo CI, 7|Naphthyridin-2-yl)ethyl)-3-methylphenyl) (piperazin-1-yl)methanone; 4-(2-(5-amino-8-methylbenzo| SHI, 7UInaphthyridin-2-yl)ethyl)-3 -methyl-

M-(2-(pyrrolidin-1-yl)ethyl)benzamide; 4-(2-(5-amino-8-methylbenzo (1, 7|Inaphthyridin-2-yl)ethyl)-M-(2-aminoethyl)-3Z-methylbenzamide; 4-(2-(5-aminobenzo|ЦІ1) , U-Naphthyridin-2-yl)ethyl)-M-(2- (dimethylamino)ethyl)-M, 3-dimethylbenzamide; 4-(2-(5-amino-Y-methylbenzo DY, 7|naphthyridin-2-yl) ethyl)-

M-(2-(dimethylamino)ethyl)-M-methylbenzamide; 2-(4-(2-(5-aminobenzo|D|I1,7UInaphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol;. 2-(4-butoxyphenethyl)-8-methylbenzo DI, 7-Naphthyridin-5-amine; 2-(2-(biphenyl-4-yl)ethyl)-8-methylbenzo|(DCI1,7|naphthyridin-5-amine; 2-(1,3-dihydroisobenzofuran-1-yl)methyl)-8-methylbenzo , 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(2-methylallyloxy)phenethyl)- benzoic acid, 7-Naphthyridin-5-amine; 2-(4-(Isopentyloxy)phenethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine;

4-(2-(5-amino-8-methylbenzo DP, 7-Naphthyridin-2-yl)ethyluphenyl-propyl-carbonate; ethyl 5-(4-(2-(5-amino-8-methylbenzo) SHI, 7|naphthyridine- 2-yl)ethylphenoxy)-pentanoate; 2-(4-(cyclopentyloxy)phenethyl)-8-methylbenzo ХІ, 7|Inaphthyridin-5-amine; 2-(4-(cyclobutylmethoxy)phenethyl)-8- methylbenzo ХІ, 7 |Inaphthyridin-5-amine; 8-methyl-2-(4-(2- morpholinoethoxy)phenethyl)benzo| DI, 7|Inaphthyridin-5-amine; 2-(4-(2-(5-amino-8- methylbenzo ЦІ1,7|Inaphthyridin-2-yl)ethyluphenoxy)-1-phenylethanone; 5-(4-(2-(5-amino-8- methylbenzo ЦІ1,7|Inaphthyridin-2-yl)ethyluphenoxy)pentanoic acid; 2 -(4-(2-(5-amino-8- methylbenzo ЩХ1,7|Inaftyridin-2-yl)uethylufenoxy)ethanol; 2-(4-(2-(5-amino-8-methylbenzo Щ/1,7) |Inaphthyridin-2-ylluethylphenoxy)-M,M-dimethylacetamide; 8-methyl-2-(2-methyl-4-(2-morpholinoethoxy)phenethyl)benzo| DI, 7|Inaphthyridin-5-amine; 2-(2 -(4-(2-(5-amino-8-methylbenzo)/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethanol; diethyl 3-(4-(2-(5- amino-8-methylbenzo TSI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate; 3-(4-(2-(5- amino-8-methylbenzo (1,7-inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonic acid; 2-(4-butoxy-2-methylphenethyl)-8-methylbenzo DCP, 7-Naphthyridin-5-amine; 2-(4-(2-(5-aminobenzo|DI1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 2-(4-(2-(5-aminobenzo|D|I1,7UInaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; ethyl 5-(4-(2-(5-amino-8-methylbenzo DP, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate; 5-(4-(2-(5-amino-8-methylbenzo|SHI, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoic acid; 2-(4-(2-(5-amino-8-methylbenzo C(1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 4-(2-(5-amino-1-methylbenzo DY, 7|Naphthyridin-2-ylethyluphenyl ethyl carbonate; methyl 4-(4-(2-(5-amino-Y-methylbenzo DP, 7|Naphthyridin-2-yl)ethyluphenoxy)butanoate; 4-(4-(2 -(5-amino-8- methylbenzo C1,7|Inaphthyridin-2-yl)uethylufenoxy)butyric acid; yl)ethyl)-3-methylphenoxy)butyric acid; 2-(4-(isopentyloxy)-2-methylphenethyl)-8-methylbenzo DCP, 7|Inaphthyridin-5-amine; 4-(2-(5-amino- 8-methylbenzo|D/I1, 7UInaphthyridin-2-yl)/ethyl)phenyl-hexyl-carbonate; 2-(2,4,6-trimethyl-phenethyl)benzo (1, 7|Inaphthyridin-5-amine; (5 -amino-2-(2,4-dimethylphenethyl)-benzo|1,7Inaphthyridin-8-yl)umethanol; diethyl /3-(2-(4-(2-(5-amino-8-methyl-benzo)) 7-Naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)propylphosphonate; diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo)CH, 7|Naphthyridin-2-yl) ethyl)-3-methylphenoxy)ethoxy)ethoxy)-propylphosphonate; 4-(2-(5-amino-8-methylbenzo DP, 7|Inaphthyridin-2-yl)ethyl)-3-methyl phenyl dimethylsulfamate; (5-amino-2- (4-(dimethylamino)phenethyl)benzo (1, 7|Inaphthyridin-8-yl)methanol; 2-(4-(dimethylamino)phenethyl)-8- methylbenzo SH, 7|Inaphthyridin-5 -amine; /4-(2-(5-amino-1-methylbenzo H(1,7|Inaphthyridin-2-yl)ethyl)uphenol; 1-(4-(2-(5-amino-8-methyl- benzo|CI1, 7UInaphthyridin-2-yl)uethyluphenyl)ethanone; 2-(4- ((dimethylamino)methyl)phenethyl)-8-methylbenzo| 1,7UInaphthyridin-5-amine; 2-(4-(1- (dimethylamino )ethylphenethyl)-8-methylbenzo|DI1,7|naphthyridin-5-amine; 1-(4-(2-(5-amino-8-methylbenzoSHII1,7|Inaphthyridin-2-yl)ethyl)phenyl)ethanone oxime; 8-methyl-2-(4- ((methylamino)methyl)phenethyl)-benzoS/1,7Inaphthyridin-5-amine; )ethyl)benzylamino)ethanol; 8-methyl-2-(4-(pyrrolidin-1-ylmethyl)phenethyl)-benzo DI, 7-Inaphthyridin-5-amine; 2-(3,4-dimethoxyphenethyl)-8-methyl-benzo DP, 7-Naphthyridin-5-amine; 2-(1-(4-(2-(5-amino-8-methylbenzoShry), 7|Naphthyridin-2-yl)ethyl)uphenyl)ethylamino)ethanol; 1-(4-( 2-(5-amino-8-methylbenzo DP, 7-Naphthyridin-2-yl)/ethylphenyl)ethanol; 8-methyl-2-(4-(oxazol-5-ylopheneethyl)benz o DP, 7|Inaphthyridin-5-amine; 3-(1-(4-(2-(5-amino-8-methylbenzo|DI, 7|Inaphthyridin-2-yl)ethyluphenyl)ethylamino)-propanenitrile; (2K)-2-(1-(4-( 2-(5-amino-8-methylbenzo (1, 7|Inaphthyridin-2-yl)ethyl)phenyl)-ethylamino)propan-1-ol; 8-methyl-2-(4-(1-(piperazin-1 -yl)oethylufenethyl)-benzo DP, 7|Inaphthyridin-5-amine; ((25)-1-(1-(4-(2-(5-amino-8- methylbenzo ЦІ1,7|Inaphthyridin-2-yl) )ethylphenyl)ethyl)pyrrolidin-2-ylmethanol; , Me-dimethylethane-1 2-diamine; 3-(1-(4-(2-(5-amino- 8-methylbenzo ХИ, 7|Inaphthyridin-2-yl)ethyluphenyl)ethylamino)upropanoic acid; 8-methyl- 2-(4-(1-(4-methylpiperazin-1-yl)uethylufenethyl)benzo DP, 7|Inaphthyridin-5-amine; M2-(1-(4-(2-(5-amino-8- methylbenzo| C1,7|Inaphthyridin-2-yl)ethyl)phenyl)ethyl)-M',M'-dimethyl-propane-1 2-diamine; 8-methyl-2-(4-(1- (2-(pyridine- 4-yl)uethylamino)ethyluphenethyl)-benzo|ЦІ1, 7|Inaphthyridin-5-amine; M1-(1-(4-(2-(5-amino-8-methylbenzo|Ц1,7|Inaphthyridin-2-yl) )ethyl)phenyl)ethyl)-Me, Me-diethylethane-1 2-diamine, 2-(4-(dimethylamino)-2-methylpheneti l)-8-methylbenzo DY, 7-Naphthyridin-5-amine; 1-(1-(4-(2-(5-amino-8- methylbenzo Х/1,7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)pyrrolidine-3-carboxylic acid; 4-(1-(4- (2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)phenyl)ethylamino)phenol; 1-(1-(4-(2-(5-amino-8-methylbenzo) SHI) .

Compounds of Formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, and pharmaceutical compositions provided herein also include all suitable isotopic variants of such compounds, and their pharmaceutically acceptable salts, solvates, M-oxides , prodrugs and isomers, and pharmaceutical compositions. An isotopic variant of a compound provided herein, or a pharmaceutically acceptable salt thereof, is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that normally found in nature Examples of isotopes that may be incorporated into the compounds provided herein and pharmaceutically acceptable salts thereof include, but are not limited to, hydrogen, carbon, nitrogen, and oxygen isotopes such as 2H, 3H, 7, 196, 140, 15M , 170, 180, 555, 18E,

З6С| and 123|, Certain isotopic variants of the compounds provided herein and pharmaceutically acceptable salts thereof, for example, those incorporating a radioactive isotope such as UN or ""C, are useful in studies of drug tissue distribution and/ or substrate. In certain examples, HN and 146 isotopes can be used due to their ease of preparation and detection. In other examples, substitution with isotopes such as h-H may allow certain therapeutic advantages derived from greater metabolic stability, such as increased IP past half-life or reduced dosage requirements. Isotopic variants of the compounds and their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, and pharmaceutical compositions provided herein are prepared by conventional methods using the corresponding isotopic variants of suitable reagents.

Methods of obtaining compounds of Formula (I)

General procedures for the preparation of the compound of Formula (I) are described in the Examples, ip. In the described reactions, reactive functional groups, for example, such as: hydroxy, amino, imino, thio or carboxy groups, where they are desired in the final product, can be protected to avoid their unwanted participation in the reactions. Commonly used protecting groups may be used in accordance with standard practice (see, for example, T.MU.

Stoyrz ip Ogdapis Spetivigu", dhoyp U/yeu apa 5opv, 1991).

In certain embodiments, the compounds of Formula (I) disclosed herein are prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound of Formula (I) with a pharmaceutically acceptable organic acid or inorganic acid. In other embodiments, a pharmaceutically acceptable acid addition salt of the compound

Formula (I) disclosed in this description is prepared by reacting the free acid form of the compound of Formula (I) with a pharmaceutically acceptable organic base or inorganic base.

Alternatively, salt forms of compounds of Formula (I) disclosed herein are prepared using salts of starting materials or intermediates. In certain embodiments, the compounds of Formula (Her) disclosed herein are in the form of other salts, including, but not limited to, oxalates and trifluoroacetates. In certain embodiments, half salts of acids and bases are, for example, hemisulfate and hemicalcium salts.

Such pharmaceutically acceptable acid addition salts of compounds of Formula (I) include, but are not limited to, such salts as: hydrobromide, hydrochloride, sulfate, nitrate, succinate, maleate, formate, acetate, adipate, besylate, bicarbonate/carbonate, propionate, fumarate, citrate , tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalene sulfonate (eg 2-naphthalene sulfonate), hexanoate (salt, bisulfate/sulfate, borate, camsylate, cyclamate, edysylate, hesylate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, orotate, oxalate, palmitate, pamoate , phosphate/hydrophosphate/dihydrophosphate, pyroglutamate, saccharate, stearate, tannate, tosylate, trifluoroacetate and xynofoate.

Organic acids or inorganic acids used to form certain pharmaceutically acceptable acid addition salts of compounds of Formula (I) include, but are not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, such as 2-naphthalenesulfonic, or caproic acid.

Such pharmaceutically acceptable base addition salts of compounds of Formula (I) include, but are not limited to, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

In certain embodiments, the free acid or free base forms of the compounds of Formula (I) disclosed herein are prepared from the corresponding base addition salt or acid addition salt, respectively. For example, a compound of Formula (I) in acid addition salt form is converted to the corresponding free base by treatment with an acceptable base (by way of example only, ammonium hydroxide solution, sodium hydroxide, and the like). For example, a compound of Formula (I) in base addition salt form is converted to the corresponding free acid by treatment with an acceptable acid (by way of example only, hydrochloric acid, etc.).

In certain embodiments, the compounds of Formula (I) in their unoxidized form are obtained from the M-oxides of the compounds of Formula (I) by treatment with a reducing agent (for example only sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an acceptable inert organic solvent (by way of example only, such as acetonitrile, ethanol, aqueous dioxane, or the like) at 0-80°C.

In certain embodiments, the prodrug derivatives of the compounds of Formula (I) are prepared by methods known to those skilled in the art (eg, for further details see Zashptsipieg ei ai., (1994), Viogdapis apa Meadisipa! Spetivigu I eCegv5, Vol. 4 , p. 1985). For example, suitable prodrugs are prepared by reacting a non-derivatized compound of Formula (I) with an acceptable carbamylating agent (by way of example only, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).

In certain embodiments, compounds of Formula (I) are prepared as protected derivatives using methods known to those skilled in the art. A detailed description of technologies acceptable for the creation of protective groups and their removal can be found in T. MU.

Steepe, "Rgoiesiiipd StoiMyrz ip Ogdapis Spetivigu", 372 edition, Udopp Umieu apa 5opv, Ips., 1999.

In certain embodiments, compounds of Formula (I) are obtained or formed as solvates (eg, hydrates). In certain embodiments, hydrates of compounds of Formula (I) are obtained by recrystallization from a mixture of aqueous/organic solvents using organic solvents such as dioxin, tetrahydrofuran or methanol.

In certain embodiments, the compounds of Formula (I) are prepared as their individual stereoisomers. In other embodiments, the compounds of Formula (I) disclosed herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereoisomers and restoring the optically pure enantiomers. In certain embodiments, separation of enantiomers is performed using covalent diastereomeric derivatives of compounds of Formula (I) or by using complexes that can be separated (for example, crystalline diastereomeric salts). Diastereomers have distinct physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.) and are easily separated by taking advantage of these differences. In certain embodiments, diastereomers are separated by chromatography, or by separation/separation techniques based on differences in solubility. The optically pure enantiomer is then recovered, together with the resolving agent, by any practical means which will not result in racemization. A more detailed description of techniques suitable for the separation of stereoisomers of compounds from their racemic mixture can be found in Ueap dasdie5, Apage Soiei, zZativei! N. U/ep, "Epapiotegv5, Nasetagiez apa Nezoishiopv", addendum U/ieu apa 5opv, Ips., 1981.

Compounds of Formula (I) are prepared by methods disclosed herein and illustrated in

Examples. In certain embodiments, the compounds of Formula (I) are prepared by a method that includes: (a) optionally converting the compound of Formula (I) into a pharmaceutically acceptable salt; (5) optionally converting the salt form of the compound of Formula (I) into a non-salt form; (c) optionally converting the unoxidized form of the compound of Formula (I) into a pharmaceutically acceptable M-oxide; (a) optional transformation of the M-oxide form of the compound of Formula (I) into its non-oxidized form; (c) optional separation of a separate isomer of the compound of Formula (I) from a mixture of isomers; () d optional conversion of non-derivatized compound of Formula (I) into a pharmaceutically acceptable prodrug derivative; and (e) optionally converting the prodrug derivative compound of Formula (I) into its non-derivatized form.

Non-limiting examples of synthesis schemes used to prepare compounds of Formula (1) disclosed herein are shown in Reaction Schemes (1)-(XI).

Scheme (I) illustrates the synthesis of benzonaphthyridines (3) by coupling substituted or unsubstituted 2-(tert-butoxycarbonyl-amino)phenylboronic acids (1) with substituted or unsubstituted C3-halopicolinonitrile derivatives (2) in the presence of a palladium catalyst. By way of example only, the halo residue of C3-halopicolinonitrile derivatives is bromine or chlorine. The functional groups (Ki, B, Az, Ba) on the benzonaphthyridines (3) are optionally further modified as disclosed herein.

Scheme (I)

In MN os khn zov) re GRA) M | va y: still Xh y? VE 5 in VE.

KI r Y Z W Y 3

Kk S K, 1 2 3

X - VgaveSi

In Sabo M

In certain embodiments, phenylboronic acids used in the synthesis of compounds

Formulas (I) are synthesized in accordance with scheme (II). In Scheme (II), substituted or unsubstituted anilines (4)

Bos-protected under basic conditions to give compound (5), and then converted to boronic acids (1) by ortho-lithiation and reaction with trimethylborate, followed by aqueous treatment.

Scheme(s)

Vos., Vos.

МН, КН Мн 00 2) Voso and UNO); в-Е 2 в Ж 0 2)В(ОМех Й 1 ий ---Яя-яяяяш 35-х -- ро 1 | р K, -B 4 5 1

Boric acids (1) are used as in scheme (I) and introduced into the reaction with substituted or unsubstituted cyanopyridines (2), which ensures the production of substituted or unsubstituted benzonaphthyridines (3).

In certain embodiments, boronic acid equivalents, including, but not limited to, substituted or unsubstituted boronate esters, are used in the synthesis of compounds

Formulas (I). Scheme (IP) illustrates the synthesis of such substituted or unsubstituted boronate esters (8), which are used as equivalents of boronic acid in the synthesis of substituted or unsubstituted benzonaphthyridines (3). In scheme (I), substituted or unsubstituted 2-haloanilines (6) are deprotected under basic conditions to give compounds (7), which are then converted into substituted or unsubstituted boronate esters (8) using a palladium-mediated catalyst. These boronate esters (8) are used as in scheme (I) and are reacted with substituted or unsubstituted cyanopyridines (2), which provides the preparation of substituted or unsubstituted benzonaphthyridines (3).

Scheme (I) хН ше It -МНо о ув, and

TI ohanmov aby AB, VO in 2 I yat (o) o) in-i r 2) VosgO - pa

Ira) 6 7 8

Hey, take it

Mo. OHM. Vo

J

Vos.

Yeyun o X 2 MN

І ХУ m c

V.D. - 2

Киле - ж --я -жшьб-5б2ит-

Plays and more 1

Kk, 8 x, - VgaiSI

In Se MZ

In certain embodiments, the substituted or unsubstituted 2-bromoanilines used in Scheme (IP) are synthesized from their corresponding substituted or unsubstituted nitrobenzene compounds as illustrated below:

Mo, MN,

VI Ee/NSI Vg xx by kg A Go - --

In certain embodiments, compounds of Formula (I) having oxygen-bonded substituents are synthesized using the methodologies described in scheme (IM).

Scheme (IM)

at-

MS M | N

With Mo. ME 00 pleo MS. M. sho MS. , M. ON r TSRVA | t Mmabn | with ---ЖЯЖ- 2 23535353- ----- ж 2 2'Ьг2335- -- -

ВИ - и- | ro

Vg VI VI 9

Well Mr

Weight H MN,

BB). MO,

MS M od | She is 2 students -- Kk. the basis of VI - -Ш2-206ОШЩШШШШШВШООН В. -They have an entrance tear! Ira) and

MN

2 ME, r

MU Ge ON hi M o ------ zidrelii ! t -4 ХУ | and

Ki r vsh for Il

In scheme (IM), benzonitrile (9) is first oxidized to M-oxide (10) with the help of metachloroperbenzoic acid (PSPA), and then converted to pyridone (11). Under specific basic conditions, pyridone (11) is selectively alkylated on oxygen to give alkoxypicolinonitrile (12).

Using palladium-mediated conditions, as in scheme (I), alkoxypicolinonitrile derivatives (12) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8)) to afford substituted or unsubstituted benzonaphthyridine (13 ) with oxygen-bound substituents. In certain embodiments, benzonaphthyridine (13) with oxygen-bonded substituents is hydrolyzed to obtain the corresponding benzonaphthiridone (14).

In other embodiments, compounds of Formula (I) having different substituents are synthesized using the methodologies described in scheme (M).

Scheme (M)

Vos. MN. os hi MN. n o UVO). know me

We Ma ef or J

SO ZY? tmeh OK I'm all I -5 1 same as F -- pt 1

Ve Ve Vi rai S

No 17 15

In scheme (M), 5-bromopyridines (15) substituted in the 2-position (shown as Co in scheme (M)) are first oxidized with meta-chloroperbenzoic acid (PSBA) to give M-oxide 16, which then converted into benzonitrile (17). Using palladium-mediated conditions, as in scheme (I), benzonitrile derivatives (17) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8), resulting in substituted or unsubstituted benzonaphthyridine (18 ) with different substituents at the C-position.In other embodiments, benzonaphthyridines having different substituents at the 2-position are prepared starting from 5-bromopyridines substituted at the C-position.

In certain embodiments, the substituent in the C-position of benzonaphthyridine (18) is a chlorine atom, and this C-chloro-benzonaphthyridine (19) is further modified to yield other substituents in

C-positions of benzonaphthyridines. Non-limiting examples of such modifications are illustrated in scheme (MI).

Scheme (MI)

MN. MN, Ku

M SI amines M M. - paradise

M | with -M(VU V») M | with Kk, ------- --- shchi ZY v- A Ve 1 || r 1 same 19 20

Mn, MH, 2 M SI Boronic acids / ich Me V

M | and complex esters | z y - 5 5-52-- Z v ! to IRai Kg

GK ra 19 21 many MN,

KE

M | Kk SI nin MU | HU E pi pi -- - E -- - we sh 19 22

In certain embodiments, as illustrated in Scheme (MI), compounds of Formula (I) having M-bonded substituents (derivatives of compounds (20) are prepared via mAb reactions by heating such chloro-derivatives (19) with various amines In certain embodiments, as illustrated in Scheme (MI), compounds of Formula (I) having carbon-bonded substituents (derivatives of compounds (21)) are prepared by Suzuki coupling, using palladium-mediated conditions, with various boronic acids or boronate esters In certain embodiments, as illustrated in Scheme (MI), compounds of Formula (I) are fluorinated by treating such chloroderivatives (19) with potassium fluoride to give (3-fluorobenzo (1,7 |-naphthyridine- 5-amine (22)).

In other embodiments, compounds of Formula (I) having different substituents are synthesized using the methodologies described in Scheme (MI).

Scheme (MI!)

BUT.

Yi A

M. I. M. Heiktyn cha »

Su non V ich Burges Vo full nvnvavanvavavaniny ia. Fri what! where -

S KE. with Kk SI Kk. 23 24 25

You.

We are MN,

With a shout hi / ka

KK dl K(abe8u xx - in folder ANKAKKAKKAKAAKAAKAAKAK td v- r 3

Ira 26

In scheme (MI), 3-chlorobenzaldehyde (23) (with a Kz substituent in the 5-position) is first converted to the corresponding hydroxylamine (24), which is then used to obtain the corresponding nitrile (25).

Using palladium-mediated conditions, as in scheme (I), nitrile derivatives (25) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8)), leading to benzonaphthyridine (26) with by different substituents in the 2-position.

In other embodiments, certain compounds of Formula (I) having oxygen-linked substituents are synthesized using the methodologies described in Scheme (MI).

Scheme (MI)

Vos. IN

МН ha VO), Ж same in th Kg ih voi Maovu vo 2 1s(or 8) in y - - tt - ---k - 5 -7 I 1 EE -x a s sy oz (Ra) SHІ 29 27 28

In scheme (MI), benzonaphthyridines with various oxygen-bonded K2 substituents in the 2-position are prepared using 3,5-dihalopicolinonitrile, such as, by way of example, 3,5-dichloropicolinonitrile (27), which is first mono-substituted with the help of an alkoxy residue, leading to the corresponding picolinonitrile (28). Then, using palladium-mediated conditions as in scheme (I), nitrile derivatives (27) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8), which leads to the preparation of benzonaphthyridine (29) with by various oxygen-bound substituents in the 2- position.

In certain embodiments, compounds of Formula (I) having hydroxy substituents, including benzonaphthyridines with various hydroxy substituents in the 2-position, are prepared using the synthetic route shown in Scheme (IX).

Scheme (IX) o- ka VaVg M TSRVA ku ----- ---nl-- - 24 AH

Vg on VI OV VI OVp 31 32

Vos.

MN ru MN.

M.

KI and sh7 with tTMesM MS ik 2 1(or8) - - p

IRAI Kk

Vg OVp 1 TSI ro 33 Ka

Mn, i Kk

But FIG. M | With - and - -is --yulsh- -

I: Mr

Kt -

In scheme (IX), a 5-halopyridin-3-ol, such as, by way of example only, 3,5-bromopyridin-3-ol (30), is benzyl-protected at the hydroxyl group, leading to compound (31), which is then converted into the corresponding M-oxide (32). M-oxide (32) is further converted to nitrile (33). Then, using palladium-mediated conditions as in scheme (I), nitrile derivatives (33) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8), leading to benzonaphthyridine (34), which, after hydrogenation, provides benzonaphthyridine (35) with a hydroxyl substituent in the 2-position.

In other embodiments, certain compounds of Formula (I) having carbon-bonded substituents, including benzonaphthyridines with various carbon-bonded substituents in the 2-position, are prepared using the synthetic route shown in Scheme (X).

Scheme (X)

Vos.

MN same: von), We, y

Me M Boronic acids / Me M Kk Х i(or8 M - -x complex esters of Me (or 8) si sZ (Ra) Viti - 21 36 37

In scheme (X), a 3,5-dihalopicolinonitrile such as, by way of example, 3,5-dichloropicolinonitrile (27) is first mono-substituted using one equivalent of boronic acid/ester, thus affording the corresponding picolinonitrile ( 36). Using more energetic palladium-mediated conditions as in scheme (I), nitrile derivatives (36) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8)), leading to benzonaphthyridine (37) , having carbon-bonded substituents in the 2-position. In certain embodiments, the carbon-bonded substituent is an alkene, while in other embodiments, such alkenes are further modified by hydrogenation, resulting in benzonaphthyridines with alkyl groups in the 2-position.

In other embodiments, certain compounds of Formula (I) having different substituents, including benzonaphthyridines with different substituents in the 1-position, are synthesized using the methodologies described in Scheme (XI).

Scheme (XI) o

SE MS Mu SI

Cape PsrVA | ky tmM5skh g - 23 -7-7-4-O-sh)y - nn - -2: rya -- -

Wh Wh Wh

K, K, Kk. 38 39 40

Wasp

MN su Mn, khn,

M SI M

K-t- ich - and 5 she or 8) N. RY/S M

Y nn on - 5 5 I Y 2 2 2 2 -» k- 4 v y pi

Ira) No KA i v, Is v, 41 42

In scheme (XI), a 4-substituted 2,5-dihalopyridine, such as, by way of example only, 5-bromo-2-chloropyridine (38), is first converted to the corresponding M-oxide (39), which is then converted to the corresponding nitrile (40). Using palladium-mediated conditions as in scheme (I), nitrile derivatives (40) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8)) to afford benzonaphthyridine

(41), which has substituents in the 1-position. In certain embodiments, benzonaphthyridine (41) is further dechlorinated to yield benzonaphthyridine (42).

In other embodiments, certain compounds of Formula (I) having different substituents, including benzonaphthyridines with different substituents in the 2-position, are synthesized using the methodologies described in scheme (XIII).

Scheme (XII)

You are here at the UN

KU Mn - vn 2 gu U in syu. ме ох и и Мих шк: РЖРФРВ), ше ак: 1 sаbo в ОН - пт | z t N y: a Ki - m hi U SHI E; si V si I RF VYK

Kk 25 26

In Scheme (XII), 2,3-dihalopyridines substituted in the 5-position (43), such as, by way of example only, (5,6-dichloropyridin-3-ylmethanol) are first converted to the corresponding nitrile (25). Using palladium- mediated conditions as in scheme (I), nitrile derivatives (25) are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8)), resulting in benzonaphthyridine (26) having substituents in 2- position.

Various 3-halo naphthyridines are prepared according to general methods as shown in the HIPI scheme.

Scheme (XII)

Sun. 7 p.m

Ku - vien

MN" MN. 1 (or VN I: I

I I (or 8) CHU Mi fluorination or M

MS. and MO I with Ra) - r. r I y: | and

VI Kg r Kg i from 45 46

In Scheme (XII), using palladium-mediated conditions as in Scheme (I), 3,6-dihalo-2-cyanopyridines such as, by way of example, 3-bromo-b-chloropicolinonitrile, are coupled with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8)), which leads to the preparation of benzonaphthyridine (45), which has halogen substitutions in the C-position. Additional halogen exchange of benzonaphthyridine (45) provides the preparation of benzonaphthyridine (46) with various halogen substituents in the C-position.

In other embodiments, certain compounds of Formula (I) are synthesized using the methodologies described in Scheme (Scheme).

Scheme (CHEM)

what MS. ЯМ x 5, ХХ shk--ky || | si a sroMeom

S ot KO ziyauya zazeku 50 Y ru va che OS vd stv

With | where are THREE heh

HeVgaboyi Fr KU | re 47 87 cho 5 Kk

Led by MN WE, MN. "Eron M I Mm7 2 ade 830 sa Xh po shhe s 1 babo ZO Vi | B t, O.R vi 4 Language (Ra - LV z

Cr 5

In the scheme (CHEM), aryl bromides or aryl iodides (47) substituted by various Kz" groups are coupled with triethyl(ethynyl)silane (or its equivalents) using palladium-mediated conditions, which provides the compound 48. After removal of the silyl- protecting group, acetylene derivatives (49) are coupled with 3,5-dichloropicolinonitrile (50) using palladium-mediated conditions to afford 3-chloro-2-cyanopyridines (51). Derivatives of 51 such as, by way of example only, 3-chloro-5-(phenylethynyl)picolinonitrile is combined with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8)) to give benzonaphthyridine (52). Compound 52 is then subjected to hydrogenation conditions, which leads to the preparation of benzonaphthyridines 53 with different substituents in the Kg position.

In other embodiments, certain compounds of Formula (I) are synthesized using the methodologies described in Scheme (XM).

Scheme (XM)

My

Ve or io; XX school Who are you?

S ia ZK KO In shsi s sis sa

And I will withdraw 5 to TV GRI) that day

Z I yah Ra Z khm. With and their Z -k pie 49 i vu

Dos

My "S u

Mine - vyaen M? in

But IS «s hu x Riabo 6 ON - ss I mon ! from nina vyk TKU

TRU with Z ka 5

In scheme (XM), aryl bromides or aryl iodides (47), substituted by various Kz" groups, are coupled with triethyl(ethynyl)silane (or its equivalents) using palladium-mediated conditions, which provides the compound 48. After removal of the silyl- protecting group, acetylene derivatives (49) are coupled with 3,5-dichloropicolinonitrile (50) using palladium-mediated conditions to afford 3-chloro-2-cyanopyridines (51). Derivatives of 51 such as, by way of example only, 3-chloro-5-(phenylethynyl)picolinonitrile is reduced to the corresponding 3-chloro-5-phenethylpicolinonitrile (54) under hydrogenation conditions. Compound 54 is combined with substituted or unsubstituted boronic acids (1) (or substituted or unsubstituted boronate esters (8 )), which leads to the preparation of benzonaphthyridines 53 with various substituents in the Kg position.

Benzonaphthyridines with various substitutions can be further converted into other functional groups using standard organic transformations. In certain embodiments, certain compounds of Formula (I) are synthesized using the methodologies described in scheme (XMI).

Scheme (XMI)

MN, MN,

M | M alkyl halides 7 | M chloroformate with he -eB8B5- in es | ov I

Ki r | he and p 3 56

MN that M

M | va sia xx, le V zv | ХОВ,

And | From amine alcohols MH,

Kitty ru r son M i z 57 i z

Kitty - 59 - M-woo woo

MN, 2 M

M x zhd

J Hu

Mn, V r | rya 61 DV"

M | . MN, kush s - rve aboalkyl|. MINY m? | M,

Se and ru uh (in; in Ho Bez

Am I 6? and live

Kk

For example, in scheme (XMI), benzonaphthyridines bearing a hydroxyl group (55) are converted to the corresponding esters or carbonates (56). For example, benzonaphthyridines bearing a carboxylic acid group (57) are converted into the corresponding esters (58) or amides (59). For example, benzonaphthyridines bearing an aldehyde or ketone group (60) are converted into the corresponding amines (61 or 62). These benzonaphthyridines can be further modified using standard organic transformations.

In certain embodiments, certain compounds of Formula (I) are synthesized using the methodologies described in Scheme (Scheme).

Scheme (CHMII)

MN, MN,

M | M M | Co

RESTORATION aa and. NON.S-i va | ME news, | V on De 63 a

MN lo dk, A

IOI M | p I) Wittig reaction M | r y: y: 2UN.RaIS yati and Z Miy

Not | in en tk en SHHI | in 65 66

In the scheme (CHMI), benzonaphthyridines with different substitutions are further converted into different functional groups through standard organic transformations. For example, benzonaphthyridines bearing an ester group (63) are converted to the corresponding alcohol (64) by reduction using standard reducing agents. Compound 64 is oxidized to the corresponding aldehyde (65), which is further alkylated using the Wittig reaction (M/NChid heasiop) followed by hydrogenation to give derivatives 66. These benzonaphthyridines can be further modified using standard organic transformations.

In certain embodiments, certain compounds of Formula (I) are synthesized using the methodologies described in scheme (XMI).

Scheme (HMI!)

Mn, Mn,

Mt z kre i: Di restoration same: Fr

OH ro NMT r 67 68

Mn, Mn,

M. Mo. MU Ma,

HOW to restore | ГБ ko 7 now and i 2 Ж 2 2 69 70

In the (CHEMISTRY) scheme, benzonaphthyridines with different substitutions are further converted into different functional groups through standard organic transformations. For example, benzonaphthyridines bearing a nitro group (67) or a cyano group (69) are converted to the corresponding amine (68) or methyl amine (70) by reduction using standard reducing agents. These benzonaphthyridines can be further modified using standard organic transformations.

In certain embodiments, certain compounds of Formula (I) are synthesized using the methodologies described in Scheme (XIX).

Scheme (XIX)

Boye pi MN hE nn

S ay dya Mi, ch od Me ; PIGA IOM - p. 5

SI Ve TS" Me m. and; ON ievbo ZON Mch 5 ok 000 pn | friday i me do garden and "t . (her s, VE beer ! s s IRO SI zi - gra vk sha | Kk 7 ; r. 7 B 73 Z in

In scheme (XIX), 2,3-dichloro-5-methylpyridine (71) is converted into the corresponding nitrile (72). Alcohol 73 is formed under the conditions of Aldol condensation, where compound 72 is introduced into the reaction with aldehyde or ketone.

Derivative compounds 73 are then combined with boronic acids (1) or boronate esters (8), which leads to the preparation of benzonaphthyridine (74).

The following examples are presented to illustrate, and not to limit, the compounds of Formula (I) provided herein and the preparation of such compounds.

Pharmacology and application

When a foreign antigen challenges the immune system, it responds by launching a protective response characterized by the coordinated interaction of both the innate and acquired immune systems. These two interdependent systems meet two mutually exclusive requirements: speed (provided by the innate system) and specificity (provided by the acquired system).

The innate immune system serves as the first line of defense against invading pathogens, keeping the pathogen in check while adaptive responses are formed. It is launched in the minutes of infection in an antigen-independent way, reacting in a broadly conservative way to pathogens (although it is not non-specific, and can distinguish its own active agents from pathogens). Critically, it also creates an inflammatory and co-stimulatory environment (sometimes called a danger signal) that enhances the adaptive immune system and directs (or directs) the cellular or humoral responses most appropriate to combat the infectious agent. The development of TIC modulators for therapeutic targeting of innate immunity has been reviewed (see Maiige

Medisipe, 2007, 13, 552-559; Ogyd Oizsomegu Todau: Tnegaretsiis eiaiediev, 2006, 3, 343-352 and documents

Ittypo!iodu, 2005, 174, 1259-1268).

The acquired response becomes effective over days or weeks, but ultimately provides the precise antigenic specificity required for complete elimination of the pathogen and creation of immunological memory.

Mainly, this is mediated by T and B cells that have undergone germline gene rearrangement and are characterized by specificity and long-term memory. However, it also involves the phenomenon of reinforcement of elements of the innate immune system, including phagocytes with canonical functions (macrophages, neutrophils, etc.) and granulocytes (basophils, eosinophils, etc.), which engulf bacteria and even relatively large protozoan parasites. Once an acquired immune response has been primed, the next exposure to the pathogen leads to its rapid elimination thanks to a highly specific memory created by the cells, which is quickly activated after the next exposure to their familiar antigen.

Autoimmune diseases characterized by a humoral or autoantibody response to a self-antigen (just as an example, Graves' primary hyperthyroidism with antibodies to the TZN receptor), or a cellular response in which immune cells destroy non-immune cells from which the self-antigen originates ( just as an example, the thyrocyte (Hashimoto's thyroiditis) or the P islet cell of the pancreas (type 1 diabetes). Many autoimmune diseases are a combination of both phenomena, for example, Hashimoto's disease and type 1 diabetes also have auto-antibodies, anti-thyroid peroxidase ( TRO) or anti-glutamic acid decarboxylase (SAB)/Islet cell. Autoimmune diseases often have an inflammatory component, including, but not limited to, increases in adhesion molecules (as just one example, vascular endothelial adhesion molecule type 1 (MCAM-1), and altered leukocyte adhesion to the vasculature, such as, but not limited to, colitis, systemic lupus, systemic sclerosis, and vascular complications of diabetes.

Toll-like receptors (TCs) are type-I transmembrane proteins characterized by an extracellular M-terminal leucine-rich repeat (ECI) domain followed by a cysteine-rich region, the TM domain, and an intracellular (cytoplasmic) tail that contains a conserved domain called the Toll/II -1 receptor (TIC) domain. TICs are type recognition receptors (RECs) that are expressed primarily on cells of the immune system, including, but not limited to, dendritic cells, T lymphocytes, macrophages, monocytes, and natural killer cells. The HA domain is important for ligand binding and associated signaling and is a common feature of RECs. The TIC domain plays an important role in protein-protein interactions and is associated with innate immunity. The TIC domain also unites the larger II/-1 A/LIC superfamily, which consists of three subgroups. Members of the first group contain immunoglobulin domains in their extracellular regions and include 1-1 and 1-18 receptors and accessory proteins, as well as 512. The second group includes TIC. The third group includes intracellular adapter proteins that are important for signaling.

TICs are a group of type recognition receptors that bind to pathogen-associated molecular patterns (RAMPR5) from bacteria, fungi, protozoa and viruses, and act as the first line of defense against invading pathogens. TICs are important for inducing the expression of genes involved in inflammatory responses, and TIs and the innate immune system are an important step in the development of antigen-specific acquired immunity.

Adaptive (humoral or cellular) immunity is related to the TIC signal mechanism of innate immunity. Innate immunity is a protective cellular immune response that functions rapidly to combat adverse environmental factors, including, but not limited to, bacterial or viral agents. Adaptive immunity is a slower response that involves the differentiation and activation of naïve T lymphocytes into T helper 1 (TA) or T helper 2 (T2) cell types. TA1 cells mainly contribute to cellular immunity, while T2 cells mainly contribute to humoral immunity. Although primarily the host's defense system, pathological expression of innate immune signals from the TIC pathway are involved in the initiation of autoimmune-inflammatory diseases.

All TIs likely function as either a homodimer or a heterodimer in the recognition of specific, or a set of specific, molecular determinants present on pathogenic organisms, including bacterial cell surface lipopolysaccharides, lipoproteins, bacterial flagellins, bacterial and viral DNA, and viral RNA. The cellular response to TIC activation includes the activation of one or more transcription factors, which leads to the production and secretion of cytokines and costimulatory molecules, such as interferons, TME-, interleukins, MIR-1 and MOR-1, which contribute to the destruction of pathogens and cleansing from pathogenic invasion.

TIC spatial expression coincides with the surrounding interface of the host. Although only a few others

Toll-like proteins have been cloned in Ogozorpia, a family of human TIs consisting of at least 11 members, THK1-TK11, which causes duplication of different biological responses due to differences in cellular expression and the signaling pathways they initiate. Each of the TICs is expressed on different subsets of leukocytes, and each of the TICs is specific in its expression pattern and RAMP sensitivity and detects different subsets of pathogens, which allows for close surveillance by the immune system.

Toll-like receptor 1 (TI K1)

TIC is located on chromosome 4ri4 and its sequence encodes a putative 786-amino acid (aa) protein with 18 M-terminal IEEs and a calculated molecular weight of 84 kDa. TI K1 is most closely related to TI Kb and TI K10 with 68 95 and 48 95 total (aa) sequence identity, respectively.

YES mRNA is ubiquitously expressed and found at a higher level than other TIBs. Of the major leukocyte populations, TIK1 is most expressed by monocytes, and is also expressed by macrophages, dendritic cells, polymorphonuclear leukocytes, B, T, and MK cells. Two different transcript sizes are observed for TI K1, suggesting that alternative splicing of the mRNA occurs to generate two different forms of the protein. In addition, the expression of TI K1 mRNA and protein is positively regulated in monocytic leukemic (TNR-1) cells during PMA-induced differentiation. TIK1 expression is positively regulated by autocrine 1-6, and its level is also increased by IEM-ub, I--10 and TME-a. However, the level of TI K1 does not depend on the influence of gram-positive and gram-negative bacteria. By the way, TI K1 expression by monocytes and granulocytes is negatively regulated after exposure to gram-negative bacteria. TI K1 forms a heterodimer with TI K2.

TIC also heterodimerizes with TI K4, which inhibits the activity of TI KA.

Toll-like receptor 2 (TI 2)

TIK2 is located on chromosome 4431-32 and encodes a putative 784 (aa) protein with 19 M-terminal IICs and a calculated molecular weight of 84 kDa. TI K2 is most closely related to TI Kb with 31 95 total (aa) sequence identity.

TI K2 mRNA expression is observed in the brain, heart, lungs, spleen, and tissues and is highest in RVI, particularly of myelomonocytic origin. However, two transcripts of different sizes are observed for TI K2, suggesting that alternative mRNA splicing occurs. In addition, expression of TI K2 mRNA and protein is positively regulated in monocytic leukemic (TNR-1) cells during PMA-induced differentiation. TI.K2 is positively regulated by autocrine 1-6 and TME-a,

IS-18 and I--10. TI K2 mRNA expression increases after exposure to gram-positive and gram-negative bacteria. THK2 forms heterodimers with TI K1, TI Kb, and possibly TI K10, and each complex is particularly sensitive to subsets of TIIK2-bound RAMPs. TI 2K2 complexes recognize a wide range of RAMPs, mainly from bacteria. These include, but are not limited to, lipoarabinomannan (GAM), lipopolysaccharides (I RB5), lipoteichoic acid (I TA), peptidoglycan (ROM), and other glycolipids, glycoproteins, and lipoproteins. TII K2 complexes are also capable of detecting viruses, including, but not limited to, measles virus (MM), human cytomegalovirus (HCMV), and hepatitis C virus (HCV) and fungal RAMPs, including, but not limited to, zymosan .

TSKa2 recognizes a wide range of lipoproteins/lipopeptides from various pathogens, such as, for example, only gram-positive bacteria, mycobacteria, Tgurapozota sgili, fungi and Tgeropeta. In addition, TI K2 recognizes GR5 preparations from non-enterobacteria, such as, for example, only I eriozriga ipiegtodapv,

Rogrpugotopaz dipdimaii5 and Neuiisobasieg Ruiogi. TI.K2 complexes are capable of both detecting non-self types and detecting altered self-types, such as those displayed by dead cells. TI K2 is recruited to phagosomes and participates in the internalization of microbial products by cells.

Toll-like receptor C (TI KZ)

TAZ is located on chromosome 4435 and encodes the sequence of a putative 904 (aa) protein of 24

M-terminal GE and a calculated molecular weight equal to 97 kDa. TI KZ is most closely related to TIC5, TIC7, and TIC8, in each case with 2695 total (aa) sequence identity.

TIKZ mRNA is expressed at a high level in the placenta and pancreas. TiICkZ is expressed by dendritic cells, T and MK cells. However, two transcripts of different sizes are observed for TI KZ, suggesting that alternative splicing of the mRNA occurs to generate two different forms of the protein. In addition, RMA-differentiated TNR-1 TI KZ is moderately positively regulated by autocrine IEM-u, 1-15, 1-6, 11-10 and TME-sa. The level of TI KZ mRNA increases after exposure to gram-negative bacteria and to an even greater extent in response to gram-positive bacteria. By the way, the expression of TI KZ increases in monocytes and granulocytes under the influence of gram-negative bacteria.

TSKZ forms a homodimer and recognizes viral double-stranded RNA (dlRNA). Although it is generally accepted that

TKs are expressed on the surface of cells, but these TKs are sensitive to internal RAMPs, such as dlRNA in the case of TI KZ, are localized intracellularly in the lysosomal compartment.

Toll-like receptor 4 (TI 4)

TK. is located on chromosome 9432-33, and shows a high degree of similarity with atoiii throughout the entire (aa) sequence. The TI K4 sequence encodes an 839 (aa) protein with 22 M-terminal and KE regions and a calculated molecular weight of 90 kDa. TI K4 is most closely related to TI K1 and

TIC, in each case with 25 95 total (aa) sequence identity.

Ip mimo, mRNA TIC. is expressed as a single transcript, and is found at the highest level in the spleen and RVI. Of the RVI populations, TI K4 is expressed by B cells, dendritic cells, monocytes, macrophages, granulocytes, and T cells. TIIK4 is also expressed in myelomonocytic cells and is highest in mononuclear cells. Ip migo, TI Kk mRNA expression. and protein is positively regulated in TNR-1 cells during PMA-induced differentiation. TI K4 is moderately positively regulated by the autocrine IEM, I--1f8. The expression of TI CA mRNA in TNR-1 cells does not depend on the influence of gram-positive and gram-negative bacteria. By the way, the expression of TI K4 by granulocytes and monocytes is positively regulated under the influence of gram-negative bacteria.

TIK4 forms a homodimer and requires the extracellular association of an additional component, MO-2. Although

TK2 complexes are able to recognize lipopolysaccharides (I P5), TI K4 is usually considered a receptor

And RB5. However, MO-2-bound TI K4 homodimers do not bind I P5 directly. And P5 must first be bound by soluble RB5-binding protein (IBP). BP is then bound by soluble or ORI-bound CO14. Additional cell-type-dependent components necessary for the detection of I! P5 with the help of TI K4 include SHSK4, ZOBE-5, CO55, various heat shock proteins (HTS), and complement receptors (CK). The TI K4 complex also recognizes several other bacterial RAMPs, including I TA.

In addition, the TI CA complex recognizes viruses, including respiratory syncytial virus (RSV), hepatitis C virus (HCV), and murine mammary tumor virus (MMV). The TI K4 complex can also recognize endogenous ligands, for example, heat shock proteins (H5PbO and H5P7O), fibrinogen, domain A of fibronectin, oligosaccharides of hyaluronic acid, heparan sulfate, surface protein (5P-

A), and B-defensins. TI K4 also forms heterodimers both with TI K5, which increases its activity, and with TI K1, which inhibits its activity.

Toll-like receptor 5 (TI 5)

TIC5 is located on chromosome 1441-42, and the gene encodes a putative 858 (aa) protein with a calculated molecular weight of 91 kDa. It is most closely related to TI KZ with 26 95 total (aa) sequence identity.

However, TI K5 mRNA is expressed as a single transcript in the ovary, prostate, and RVI. TI K5 is expressed by several populations of RVI, with the highest expression found in monocytes. TI K5 is also expressed on the basolateral side of intestinal epithelial cells and intestinal endothelial cells of the subepithelial compartment. In addition, TIK5 is positively regulated in PMA-differentiated TNR-1 cells by autocrine 1I--6, 11-10 and TME-a, and its level is increased by IEM-UV. TI K5 mRNA expression increases after exposure to gram-positive and gram-negative bacteria. By the way, the expression of TI K5 by granulocytes and monocytes is negatively regulated under the influence of gram-negative bacteria. TIK5 forms a homodimer, as well as a heterodimer with TI K4. Both complexes function to recognize the flagellin protein from flagellated bacteria. Expression of human TK5 in CHO cells responds to flagellin, a monomeric component of bacterial flagella. Flagellin activates lung epithelial cells to induce the production of inflammatory cytokines. A stop codon polymorphism in TIC5 was associated with susceptibility to pneumonia caused by the flagellated bacterium I ediopePa rpeshthornpiyia.

Toll-like receptor 6 (TI Kb)

TI Kb is located on chromosome 4p14, and the sequence of TI Kb encodes a 796 (aa) protein containing 20

M-terminal KK motifs with a calculated molecular weight equal to 91 kDa. TI Kb is most closely related to TI K1!, TIC10, and TI/K2 with 6895, 4695, and 3195 total (aa) sequence identity, respectively.

Additionally, the THKb transcript is observed in the thymus, spleen, and lungs. TI Kb mRNA expression is highest in B cells and monocytes. In addition, the expression of TI Kb mRNA is positively regulated in TNR-1 cells during PMA-induced differentiation. TI Kb is moderately positively regulated by autocrine IEM,

I--18. However, TI Kb mRNA expression in TNR-1 cells does not depend on the influence of gram-positive and gram-negative bacteria. By the way, the expression of TI Kb by monocytes and granulocytes is negatively regulated under the influence of gram-negative bacteria. TIKb forms a heterodimer with TIK2. Like TIK1, TI Kb is thought to determine or increase the RAMP sensitivity of T/K2 and contribute to its ability to signal by heterodimerization.

Toll-like receptor 7 (TI 7)

THRESHING FLOOR? is located on the human Xr22 chromosome, and the TI K7 sequence encodes a 1049 (aa) protein containing 27 M-terminal I CCs with a calculated molecular weight of 121 kDa. TI K7 is most closely related to TI K8 and TI KU with 43 95 and 36 95 total (aa) sequence identity, respectively.

Additionally, TI K7 mRNA is expressed in the lungs, placenta, spleen, lymph nodes, and tonsils. TIC mRNA expression is highest in monocytes, lymphocytes, and plasmacytoid dendritic cells. Moreover, TI K7 mRNA expression is positively regulated in TNR-1 cells during PMA-induced differentiation. TI K7 is very positively regulated under the influence of 1-6 and, to a lesser extent, autocrine IEM, I--18. TI K7 mRNA expression in TNR-1 cells increases after exposure to gram-

positive and gram-negative bacteria. By the way, TI K7 expression increases after contact with gram-positive and gram-negative bacteria in monocytes and, to a greater extent, in granulocytes. TI K7 is expressed in the nucleolus. The role of TI K7 is to detect the presence of "foreign" single-stranded RNAs in the cell, as a tool for responding to viral invasion. TI K7 is a structurally highly conserved protein that recognizes guanosine- or uridine-rich single-stranded RNA (55KMA) from viruses such as human immunodeficiency virus, vesicular stomatitis virus, and influenza.

Toll-like receptor 8 (TI 8)

TC8 is located on chromosome Xra22, and the TI K8 sequence encodes a 1041 (aa) protein containing 26

M-terminal ECs with a calculated molecular weight equal to 120 kDa. TI K8 is most closely related to TI K7 and TI KU with 43 95 and 35 95 total (aa) sequence identity, respectively.

Furthermore, TI K8 mRNA is expressed in the lung, placenta, spleen, lymph nodes, bone marrow, and RVI, with the highest expression found in cells of myeloid origin, such as monocytes, granulocytes, and myeloid dendritic cells. In addition, TI K8 mRNA expression is positively regulated in TNR-1 cells during PMA-induced differentiation. TI K8 is very positively regulated by autocrine HER -18D, 11 -6, 11-10 and TME-sa, and is even more enhanced under the influence of IEM. Expression of mRNA

TIK8 in TNR-1 cells increases after exposure to gram-positive and gram-negative bacteria. By the way, expression of TI K8 by monocytes increases, and expression by granulocytes decreases under the influence of gram-negative bacteria. TI K8 is expressed in the nucleolus. The role of TI K8 is to detect the presence of "foreign" single-stranded RNAs in the cell, as a tool for responding to viral invasion. TI K8 is a structurally highly conserved protein that recognizes guanosine- or uridine-rich single-stranded RNA (55KMA) from viruses such as human immunodeficiency virus, vesicular stomatitis virus, and influenza.

Toll-like receptor 9 (TI K9)

TKU is located on chromosome Zra1, and the TI KU sequence encodes a 1032 (aa) protein containing 27

M-terminal ECs with a calculated molecular weight equal to 116 kDa. TI KU is most closely related to TI K7 and TI K8 with 36 95 and 35 95 total (aa) sequence identity, respectively.

Additionally, TCU mRNA is expressed in the spleen, lymph nodes, bone marrow, and RVE.

In particular, TI KU mRNA is expressed at the highest level in B cells and dendritic cells. Ip miigo

TCU is moderately positively regulated by autocrine IEM-u, 1-15, IS-6b, 11-10 and TME-a4 in PMA-differentiated TNR-1 cells. The expression of TI KO mRNA in TNR-1 cells does not depend on the influence of gram-positive and gram-negative bacteria. By the way, the expression of TCU in monocytes and, in particular, in granulocytes is negatively regulated in response to gram-negative bacteria. TCU forms a homodimer and recognizes unmethylated bacterial DNA. TI KO participates in the inflammatory response to bacterial

DNA and oligonucleotides containing unmethylated DNA sequences Cpo. TI KU is localized internally, perhaps in lysosomal or endocytic compartments, where it would be more likely to encounter

RAMP, including unmethylated DNA sequences of C.

TIC9 is a receptor for Spo DNA, and recognizes bacterial and viral Spo DNA. Bacterial and viral DNAs contain unmethylated SpoO motifs that confer immunostimulatory activity. In vertebrates, the frequency of CroO motifs is strongly reduced, and cytosine residues of Cro motifs are highly methylated, which leads to a decrease in immunostimulating activity. Structurally, there are at least two types of Cro DNA: B/K-type Cro DNA is a potent inducer of inflammatory cytokines such as 1-12 and TME-c;

A/O-type Cro DNA has a greater ability to induce IEMo production. from plasmacytoid dendritic cells (ROS). TCU is also involved in the pathogenesis of autoimmune diseases, and may play an important role in Graves' autoimmune hyperthyroidism and the production of rheumatoid factor by autoreactive B cells. In addition, internalization of Es by the receptor can cause TIKkO9-mediated induction of ROS IEM-co; immune complexes containing Ide and chromatin, which are involved in the pathogenesis of systemic lupus erythematosus (SLE). TCU is involved in the pathogenesis of a number of autoimmune diseases by recognizing the structure of chromatin.

Toll-like receptor 10 (TI K10)

The TAKO sequence encodes a putative 811 (aa) protein with a molecular weight of 95 kDa.

TAKO is most closely related to TIC1! and TI Kb with 4895 and 46 95 total (aa) identity, respectively.

Furthermore, TI K10 mRNA expression is highest in immune-related tissues, including the spleen, lymph nodes, thymus, and tonsils. TI K10 mRNA is most expressed on B-cells and plasmacytoid dendritic cells (PDCs). In my opinion, TI K1O0 is moderately positively regulated by autocrine IEM, 1-18, 1-6, 11-10 TMEs in PMA-differentiated TNR-1I cells.

TIK10 mRNA expression in TNR-1 cells increases after exposure to gram-positive and gram-negative bacteria. Eh mimo, monocyte expression is increased by TIC10, while granulocyte expression is decreased by gram-negative bacteria.

Toll-like receptor 11 (TI K11)

TK11 is expressed in bladder epithelial cells and mediates resistance to uropathogenic bacterial infection in mice.

As shown above, TI K2 and TI K4 recognize cell wall products of gram-positive and gram-negative bacteria, respectively; TI K5 recognizes structural epitopes of bacterial flagellin; THOSE KZ,

TIC, TIC, and TCU recognize different forms of microbial nucleic acids.

TIC domains interact with several adapter molecules containing TIC domains (MuUO88), adapter protein containing TIC domain (TICAR), IEM-a inducing adapter containing TIV domain (TKIE) and TKIE-pov bound adapter molecule (TRAM), which activate a cascade of events as a result of transcription factor induction.

TIC signaling pathways.

TICs are distributed throughout the cell. TI K1, TI K2, TI KZ and TI K4 are expressed on the cell surface, while TI KZ, TIK, TI K8 and TI KU are expressed in intracellular compartments such as endosomes. TIKZ-, TI B7-, or TI KU-mediated recognition of their ligands requires endosomal maturation and processing. When macrophages, monocytes, dendritic cells, or non-immune cells that have become antigen-presenting cells engulf bacteria by phagocytosis, the bacteria are degraded and bro DNA is released into phagosomes-lysosomes or into endosomes-lysosomes, where they can interact with TI CUs that have been recruited from the endoplasmic reticulum during nonspecific capture of Spo DNA. In addition, when viruses invade cells by receptor-mediated endocytosis, viral contents enter the cytoplasm by fusion of the viral envelope with the endosomal membrane. This leads to exposure to TI E ligands such as dlRNA, 55KMA and Cro

DNA from TI KU in phaseosomal/lysosomal or endosomal/lysosomal compartments.

In signaling pathways downstream of the TIC domain, the TIC domain-containing adapter Mu088 is important for the induction of inflammatory cytokines such as TME-o and I/-12 through all TCs. Although adapter molecules containing the TIC domain (MuO88) are common to all TICs, individual signaling pathways

TICs differ, and activation of specific TICs leads to slightly different patterns of gene expression profiles. Just as an example, activation of the TI KZ and TI K4 signaling pathways leads to the induction of type I interferons (IIF), whereas activation of the TI K2 and TI K5-mediated pathways does not. However, the activation of signaling pathways TIK, TI! K8 and TI KU and leads to the induction of type I IEM, although this occurs by means of mechanisms different from TI K3/4-mediated induction.

Once engaged, TICs initiate a signaling cascade that leads to the activation of MEkV through the primary response gene myeloid differentiation adapter protein 88 (MuO88) and the involvement of I-1 receptor-related kinase (IKAK). The Mur88-dependent pathway is analogous to I-1 receptor signaling, and it is believed that Mur88, with its C-terminal TIK domain and M-terminal death domain, associates with the TIK domain of TIK. Upon stimulation, Mu0O88 recruits IKAK-4 to the TIC through the interaction of the death domains of both molecules, and facilitates IKAK-4-mediated phosphorylation of IKAK-1.

Phosphorylation of IKAK-1 leads to the recruitment of TME receptor-associated factor 6 (TKAEb), which leads to the activation of two different signaling pathways. One pathway leads to activation of AR-1 transcription factors by activation of MAP kinase. Another pathway activates the TAKT/TAV complex, which increases the activity of the KV kinase complex (IKK). After activation, the CC complex induces phosphorylation and subsequent degradation of the MEkV inhibitor IkV, which leads to the nuclear translocation of the MEkV transcription factor and the initiation of transcription of genes whose promoters contain the MEkV binding sites of cytokines such as cytokines. The MUYUO88-dependent pathway plays an important role and is important for the production of inflammatory cytokines through all TI Ks.

Stimulation of cells expressing TI K8, such as PMVS, leads to the production of high levels of IS-12, IEM-u, IS-1, TME-o, I--6 and other inflammatory cytokines. Similarly, stimulation of cells expressing TI K7, such as plasmacytoid dendritic cells, results in the production of high levels of interferon-α (IEMa) and low levels of inflammatory cytokines. Thus, through the activation of dendritic cells and other antigen-presenting cells, the recruitment of TI K7, TI K8 or TI KU and the production of cytokines are expected to activate a variety of innate and acquired immune response mechanisms that lead to the destruction of pathogens, infected cells or tumor cells.

Compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, pharmaceutical compositions, and/or combinations presented by the authors can be used as modulators of the activity of Toll-like receptors, and are used in the treatment of a wide range of diseases and /or disorders associated with such receptors. In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are modulators of TI K7 activity and are useful in the treatment of diseases and/or disorders related to connected with TI K7. In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are agonists of TI K7 activity and are useful in the treatment of diseases and/or disorders related to connected with TI K7. In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and their isomers, as well as pharmaceutical compositions provided by the authors, are modulators of TIMK8 activity and are useful in the treatment of diseases and/or disorders related to connected with TI K8. In some embodiments, the compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are agonists of TI K8 activity and are useful in the treatment of diseases and/or disorders related to connected with TI K8.

In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of diseases and/or disorders of the respiratory organs, including but not limited to the above, asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (including aspirin- and

NSAID-induced) and dust-induced asthma, chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis, emphysema, bronchiectasis, cystic fibrosis, sarcoidosis; farmer's lung and similar diseases; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrotic complications of anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections, complications of lung transplantation; vasculitic and thrombotic disorders of the pulmonary vascular system and pulmonary hypertension; antitussive activity, including the treatment of chronic cough associated with inflammatory and secretory conditions of the respiratory tract, and iatrogenic cough, acute and chronic rhinitis, including drug-induced rhinitis and vasomotor rhinitis; annual and seasonal allergic rhinitis, including гпипий5 pegmosis (hay fever); nasal polyps, acute viral infection, including colds and infections due to respiratory syncytial virus, influenza virus, coronavirus (including ZAK5) and adenovirus.

In some embodiments, the compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and their isomers, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of dermatological diseases, including, but not limited to, psoriasis, atopic dermatitis, contact dermatitis, eczema or other dermatoses, and delayed-type hypersensitivity reactions, phyto- and photodermatitis, seborrheic dermatitis, dermatitis herpetiformis, lichen planus, Ispep 5siegosi5ei aigorpis, gangrenous pyoderma, sarcoidosis of the skin, basal cell carcinoma, actinic keratosis, discoid lupus erythematosus, pemphigus, pemphigoid, bullous epidermolysis, urticaria, Quincke's edema, vasculitis, toxic erythema, skin eosinophilia, focal alopecia, male pattern baldness, Sweet's syndrome, Weber's syndrome

Christiana, erythema multiforme, cellulitis, infectious and non-infectious; panniculitis; skin lymphoma, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders, including fixed drug-induced rashes.

In some embodiments, the compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers thereof, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of eye diseases and/or disorders, including but not limited to the above, blepharitis, conjunctivitis, including annual and spring allergic conjunctivitis, iritis, anterior and posterior uveitis; choroiditis; autoimmune, degenerative and inflammatory diseases affecting the retina; ophthalmitis, including sympathetic ophthalmitis; sarcoidosis; infections, including viral, fungal and bacterial.

In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of diseases and/or disorders of the genitourinary system, including, but not limited to, non-ESERitis, including interstitial and glomerulo-ESRitis, non-ESEotic syndrome, cystitis, including acute and chronic (interstitial) cystitis and Hanner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis, vulvovaginitis, Peyronie's disease; erectile dysfunction (in men and women).

In some embodiments, the compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of allograft rejection, including but not limited to , acute and chronic after, for example, kidney, heart, liver, lung, bone marrow, skin or cornea transplantation or after blood transfusion, or chronic graft-versus-host disease.

In some embodiments, the compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of other autoimmune and allergic disorders, including, but not limited to but not limited to, rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Crohn's disease, inflammatory bowel disease (IBD), Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, hyper-IZDE syndrome , antiphospholipid syndrome and Sazari syndrome.

In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are used in the treatment of cancer, including, but not limited to, prostate, breast tumors , lungs, ovaries, pancreas, intestines and rectum, stomach, skin and brain, and malignant neoplasms affecting the bone marrow (including leukemias) and the lymphoproliferative system, such as Hodgkin's and non-Hodgkin's lymphomas, including prevention and treatment of metastatic disease and recurrence of tumors and paraneoplastic syndromes. In some embodiments, the compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are useful as modulators of toll-like receptor activity, and are used in the treatment of neoplasias, including but not limited to, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, carcinoma, sarcoma, leukemia, renal carcinoma, Kaposi's sarcoma, myelogenous leukemia, chronic lymphocytic leukemia, and multiple myeloma.

In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of infectious diseases, including, but not limited to, viral diseases such as genital warts, common warts, plantar warts, respiratory syncytial virus (RSV), hepatitis B, hepatitis C, dengue virus, herpes simplex virus (only as an example, NOM-Y, NBM-Y, SMM or MM ), molluscum contagiosum, vaccinia, smallpox, lentivirus, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus (CMV), varicella virus (VVV), rhinovirus, enterovirus, adenovirus, coronavirus (eg, ZAKZ5B) , influenza, para-influenza, mumps virus, measles virus, papovavirus, hepadnavirus, flaviviruses, retrovirus, arenovirus (as an example only, CMV, Hunina virus, Machupo virus, Guanarito virus and Lassa fever) and filovirus (as an example only, Ebola virus or tagrid virus).

In some embodiments, the compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, pharmaceutical compositions, and/or combinations provided by the authors are used in the treatment of bacterial, fungal and protozoan infections, including but not including, but not limited to, tuberculosis and tuberculosis, leprosy, syphilis, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, leishmaniasis, infections caused by bacteria of the genus EzsPpegispia, Epiegorasieg, ZaItopeMya, Ziarpuiosossiv5, KiIerzieMPa, Rgoiecv5,

Rzeiidotopachus, Zigeriosossi5, and Spiatuaia, and fungal infections such as candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis.

In some embodiments, the compounds of formulas (I) and (IA), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers are used as immune potentiators. In some embodiments, the compounds provided by the authors are included in immunogenic compositions or used in combination with immunogenic compositions. In some embodiments, the immunogenic compositions are used as vaccines, and the compound is present in an amount sufficient to enhance an immune response to the vaccine, or an antigen mixed with the compound. The vaccine contains at least one antigen, which can be a bacterial antigen or a cancer antigen or a viral antigen. In some embodiments, compounds of formula (I) or (IA), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are included in therapeutic vaccines or used in combination with a therapeutic vaccine. In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are included in prophylactic vaccines or used in combination with a prophylactic vaccine. In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are included in, or used in combination with, therapeutic antiviral vaccines. In some embodiments, compounds of formula (I), their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers, as well as pharmaceutical compositions provided by the authors, are included in or used in combination with anticancer vaccines.

In other embodiments, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, described by the authors, are useful in the treatment of damaged or aging skin, such as scars and wrinkles.

Introduction and pharmaceutical compositions

For therapeutic uses of the compounds of Formula (I), or their pharmaceutically acceptable salts, solvates, M-oxides, prodrugs and isomers disclosed herein, such compounds are administered in therapeutically effective amounts either alone or as part of a pharmaceutical composition.

Accordingly, provided herein are pharmaceutical compositions comprising at least one compound of Formula (I) disclosed herein, pharmaceutically acceptable salts and/or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In addition, such compounds and compositions are administered alone or in combination with one or more additional therapeutic agents. Methods of administration of such compounds and compositions include, but are not limited to, oral administration, rectal administration, parenteral administration, intravenous administration, intracautery administration, intramuscular administration, inhalation administration, intranasal administration, topical administration, ophthalmic administration, or auricular administration.

A therapeutically effective amount will vary depending on, among others, the disease identified, the severity of the disease, the age and relative health of the subject, the potency of the compound being administered, the method of administration, and the desired treatment. In certain embodiments, the daily dose of the compound

Formula (I) has been shown to give satisfactory results systemically at daily doses of approximately 0.03 to 2.5 mg/kg body weight. In certain embodiments, the daily dose of a compound of Formula (I) administered by inhalation is in the range of 0.05 micrograms per kilogram of body weight (μg/kg) to 100 micrograms per kilogram of body weight (μg/kg). In other embodiments, the daily dose of a compound of Formula (I) administered orally is in the range of 0.01 micrograms per kilogram of body weight (μg/kg) to 100 milligrams per kilogram of body weight (μg/kg). The indicated daily dose in large mammals, such as humans, is in the range of about 0.5 mg to about 100 mg of a compound of Formula (I) administered by a convenient method, for example, in divided doses up to four times a day or in a controlled release form . In certain embodiments, dosage forms for oral administration comprise from about 1 to 50 mg of a compound of Formula (1).

In other aspects, this description provides methods for preparing a pharmaceutical composition that includes at least one compound of Formula (I) disclosed in this description, its or pharmaceutically acceptable salts of talaba solvates. In certain embodiments, such methods include admixing a compound of Formula (I) disclosed herein, and pharmaceutically acceptable salts and solvates thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, pharmaceutical compositions comprising a compound of Formula (I) in free form or in the form of a pharmaceutically acceptable salt or solvate, in combination with at least one pharmaceutically acceptable carrier, diluent, or excipient, are prepared by mixing, granulating, and/or coating. In other embodiments, such compositions optionally contain fillers, such as preservatives, stabilizers, wetting or emulsifying agents, dissolution accelerators, salts for regulating osmotic pressure, and/or buffers.

In other embodiments, such compositions are sterilized.

Oral dosage forms

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are administered orally as separate dosage forms, where such dosage forms include, but are not limited to, capsules, gelatin capsules, caplets, tablets, chewable tablets, powders, granules, syrups, flavored syrups, solutions or suspensions in aqueous or non-aqueous liquids, food foams or whipped masses, and liquid emulsions of the oil-in-water type or liquid emulsions of the ox-in-oil type.

Capsules, gelatin capsules, caplets, tablets, chewable tablets, powders or granules used for oral administration of at least one compound of Formula (I) are prepared by mixing at least one compound of Formula (I) (active ingredient) together with at least one excipient using conventional pharmaceutical mixing technologies.

Non-limiting examples of excipients used in the oral dosage forms disclosed herein include, but are not limited to, binders, fillers, disintegrants, lubricants, absorbents, colors, flavors, preservatives, and sweeteners.

Non-limiting examples of such binders include, but are not limited to: corn starch, potato starch, starch paste, peptized starch, or other starches, sugars, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginate acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (as examples only, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and microcrystalline cellulose), magnesium aluminosilicate, polyvinyl pyrrolidone and their combinations.

Non-limiting examples of such excipients include, but are not limited to, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, peptized starch, and mixtures thereof. In certain embodiments, the binder or excipient provided in the pharmaceutical compositions herein is present in an amount from about 50 to about 99 percent by weight of the pharmaceutical composition or dosage form.

Non-limiting examples of such disintegrants include, but are not limited to: agar-agar, alginic acid, sodium alginate, calcium carbonate, sodium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or cassava starch, peptized starch, other starches, wedges, other algins, other celluloses, gums, and their combinations. In certain embodiments, the amount of disintegrant used in the pharmaceutical compositions provided herein is from about 0.5 to about 15 percent by weight of the disintegrant, while in other embodiments, the amount is from about 1 to about 5 mass percentages of the disintegrant.

Non-limiting examples of such lubricants include, but are not limited to, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, talc, hydrogenated vegetable oil (as examples only, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, agar, silica, siloxane silica gel (AEKOZ5II. 200, manufactured by M/.K. Sgase Co., Waiitoge, Ma.), coagulated synthetic silica aerosol (sold by UOedibzza Co., Riapo, Tex.), SAV-O-5II (pyrogenic silicon dioxin - product , which is sold by Saroi So., Vob5iop, Ma55.) and their combinations. In certain embodiments, the amount of lubricants used in the pharmaceutical compositions provided herein is less than about 1 percent by weight of the pharmaceutical compositions or dosage forms.

Non-limiting examples of such diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, or combinations thereof.

In certain embodiments, tablets and capsules are prepared by homogeneously mixing at least one compound of Formula (I) (active ingredients) with liquid carriers, finely divided solid carriers, or both, and then forming the product into the desired presentation form, if necessary. In certain embodiments, tablets are obtained by compression. In other embodiments, tablets are obtained by pressing in a mold.

In certain embodiments, at least one compound of Formula (I) is orally administered as a controlled release dosage form. Such dosage forms are used to provide slow or controlled release of one or more compounds

Formulas (). Controlled release is obtained using, for example, hydroxypropyl methyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof. In certain embodiments, the controlled release dosage form is used to prolong the activity of the compound of Formula (I), reduce the frequency of dosing, and improve the patient's compliance with the treatment regimen.

The administration of the compounds of Formula (I) in the form of oral liquids, such as solution, syrups and elixirs, is carried out in metered dosage forms so that a given amount of solution, syrups or elixirs contains the calculated amount of the compound of Formula (I). Syrups are prepared by dissolving the compound in a suitable flavored aqueous solution, while elixirs are prepared by using non-toxic alcoholic vehicles. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Non-limiting examples of excipients used in oral liquids for oral administration include, but are not limited to, solubilizers, emulsifiers, flavors, preservatives, and colors. Non-limiting examples of solubilizers and emulsifiers include, but are not limited to, water, glycols, oils, alcohols, ethoxylated isosteararyl alcohols, and polyoxyethylene sorbitol ethers. Non-limiting examples of preservatives include, but are not limited to, sodium benzoate. Non-limiting examples of flavors include, but are not limited to, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners.

Parenteral dosage forms

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulations (I) are administered parenterally by various routes, including, but not limited to, subcutaneous, intravenous (including bolus), intramuscular, and intraarterial administration.

Such parenteral dosage forms are administered in the form of sterile or sterilized injection solutions, suspensions, dry and/or lyophilized products ready for dissolution or suspension in a pharmaceutically acceptable carrier for injection (reconstituted powders), and emulsions. Carriers used in such dosage forms include, but are not limited to, Water for Injection O5R; aqueous carriers such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, sodium chloride and dextrose injection, and Ringer's lactate injection; water-soluble fillers such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous excipients such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Transdermal dosage forms

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are administered transdermally. Such transdermal dosage forms include "reservoir-type" or "matrix-type" patches that are applied to the skin and worn for a specific period of time to allow penetration of a desired amount of a compound of Formula (I). By way of example only, such transmembrane devices are in the form of a dressing comprising a substrate, a reservoir containing the compound, optionally with carriers, optionally, a rate-controlling barrier for delivering the compound to the skin of the host at a controlled and calculated speed over a long period of time, and a means for fixing the device on the skin. In other embodiments, matrix transdermal compositions are used.

Compositions for transdermal delivery of a compound of Formula (I) include an effective amount of a compound of Formula (I), a carrier, and an optional diluent. The carrier includes, but is not limited to, pharmacologically acceptable solvents that can be absorbed to facilitate passage through the skin of the host, such as water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate , isopropyl palmitate, mineral oil, and their combinations.

In certain embodiments, such transdermal delivery systems include penetration enhancers to facilitate delivery of one or more compounds of Formula (I) to tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; collidone brands (Romidope, Roiumidope); urea; and various water-soluble or insoluble sugar esters such as Tuyep 80 (polysorbate 80) and Zrap 60 (sorbitol monostearate).

In other embodiments, the pH of such transdermal pharmaceutical composition or dosage form, or the tissue to which this pharmaceutical composition or dosage form is applied, is adjusted to improve delivery of one or more compounds of Formula (I). In other embodiments, the polarity of the solvent carrier, its ionic strength, or tonicity is adjusted to improve delivery. In other embodiments, compounds such as stearates are added preferably to alter the hydrophilicity or lipophilicity of one or more compounds of Formula (I) in order to improve delivery. In certain embodiments, such stearates serve as a lipid carrier for the compositions, as an emulsifying agent or surfactant, and as a delivery enhancing agent or penetration enhancing agent. In other embodiments, various salts, hydrates or solvates of the compounds of Formula (1) are used to further adjust the properties of the resulting composition.

Local dosage forms

In certain embodiments, at least one compound of Formula (I) is administered by local application of a pharmaceutical composition containing at least one compound of Formula (I) in the form of lotions, gels, ointments, solutions, emulsions, suspensions or creams. Suitable compositions for topical application to the skin are aqueous solutions, ointments, creams or gels, while compositions for ophthalmic administration are aqueous solutions. Such compositions do not necessarily contain solubilizers, stabilizers, tonicity-enhancing agents, buffers, and preservatives.

Such topical compositions include at least one carrier, and optionally at least one diluent. Such carriers and diluents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.

In certain embodiments, such topical compositions include penetration enhancers to assist in the delivery of one or more compounds of Formula (I) to tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; collidone brands (Romidope,

roiumidope); urea; and various water-soluble or insoluble sugar esters such as Tmeep 80 (polysorbate 80) and Zrap 60 (sorbitol monostearate).

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are administered by inhalation. Medicinal forms for introduction through the respiratory tract are prescribed in the form of aerosols or dry powders. Aerosol compositions for inhalation include a solution or thin suspension of at least one compound of Formula (I) in a pharmaceutically acceptable aqueous or non-aqueous solvent. In addition, such pharmaceutical compositions optionally include a powder base such as lactose, glucose, trehalose, mannitol or starch, and optionally a property modifier such as I-leucine or another amino acid, and/or metal salts of stearic acid such as as magnesium or calcium stearate.

In certain embodiments, the compounds of Formula (I) are administered directly to the lungs by inhalation using a metered dose inhaler ("MO") that uses aerosol cans containing a suitable low boiling point propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxin or other suitable gas, or

A powder inhaler (POI) is a device that uses a gas release to create a cloud of dry powder inside a container, which is then inhaled by the patient. In certain embodiments, gelatin capsules and cartridges are formulated for use in an inhaler or insufflator containing a powder mixture of a compound of Formula (I) and a powder base such as lactose or starch. In certain embodiments, the compounds of Formula (I) are delivered to the lungs using a liquid drip device, where such devices use very small nebulizer holes to spray liquid drug compositions that can then be directly inhaled into the lungs. In other embodiments, the compounds of Formula (I) are delivered to the lungs using an inhaler, where the inhaler creates aerosols of liquid medicinal compositions by using ultrasonic energy to form fine particles that can be easily inhaled. In other embodiments, the compounds of Formula (I) are delivered to the lungs using an electrohydrodynamic ("ENO") aerosol device, where such ENO aerosol devices use electrical energy to nebulize liquid drug solutions or suspensions.

In certain embodiments, a pharmaceutical composition containing at least one compound

Formula (I), or pharmaceutically acceptable salts and solvates thereof, disclosed herein also contains one or more absorption enhancers. In certain embodiments, such absorption enhancers include, but are not limited to, sodium glycolate, sodium caprate, M-lauryl-B-O-maltopyranoside, EOTA, and mixed micelles.

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are administered nasally. Dosage forms for nasal administration are prescribed as aerosols, solutions, drops, gels or dry powders.

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are administered rectally in the form of suppositories, enemas, ointments, creams, rectal foams or rectal gels. In certain embodiments, such suppositories are obtained from fat emulsions or suspensions, cocoa butter or other glycerides.

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are administered ophthalmologically as eye drops. Such compositions are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity-enhancing agents, buffers, and preservatives.

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are administered intraocularly as ear drops. Such compositions are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity-enhancing agents, buffers, and preservatives.

In certain embodiments, pharmaceutical compositions containing at least one compound

Formulas (I) are formulated as a "depot" drug. Such long-acting compositions are administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, such compositions include polymeric or hydrophobic materials (for example, in the form of an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example, in the form of a poorly soluble salt.

This description provides compounds of Formula (I), pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions containing at least one compound of Formula (I) and/or pharmaceutically acceptable salts and solvates thereof, for use in modeling TI K activity, and, thus, are used to prevent or treat diseases and/or disorders associated with TI Kc activity. In certain embodiments, such compounds of Formula (I), their pharmaceutically acceptable salts and solvates, and pharmaceutical compositions are TIAK7/ agonists, and thus are used to treat diseases and/or disorders associated with T/K7. In certain embodiments, the following compounds of Formula (I), their pharmaceutically acceptable salts and solvates, and pharmaceutical compositions are TI K8 agonists, and thus are used to treat diseases and/or disorders associated with TI 8.

Also provided herein are methods of treating a subject suffering from a disease and/or disorder associated with TI K activity, wherein the methods comprise administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, either alone or as part of a pharmaceutical composition as disclosed herein.

This description provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicinal product for the treatment of a disease or disorder associated with TI K activity. In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is used in the preparation of a medicament for the treatment of a disease or disorder associated with TIC7. In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is used in the preparation of a medicament for the treatment of a disease or disorder associated with TI B8.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for oral administration for the treatment of viral diseases and/or disorders associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for oral administration for the treatment of infectious diseases and/or disorders associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for oral administration for the treatment of bacterial diseases and/or disorders associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for oral administration for the treatment of fungal diseases and/or disorders associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for oral administration for the treatment of cancer associated with

TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for intravenous administration for the treatment of cancer associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for oral administration for the treatment of diseases and/or disorders associated with allograft rejection associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for oral administration for the treatment of genitourinary diseases and/or disorders associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for administration in the form of eye drops for the treatment of ophthalmic diseases and/or disorders associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for local administration for the treatment of dermatological diseases and/or disorders associated with TI K7 or TI K8 activity.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for local administration for the treatment of senile keratosis. In an additional embodiment, pharmaceutical compositions including at least one compound

Formulas (I) are adapted for local administration in the form of a cream for the treatment of senile keratosis.

In an additional embodiment, pharmaceutical compositions including at least one compound of Formula (I) are adapted for local administration for the treatment of basal cell epithelioma. In an additional embodiment, pharmaceutical compositions including at least one compound of Formula (I) are adapted for local administration in the form of a cream for the treatment of basal cell epithelioma.

In an additional embodiment, pharmaceutical compositions comprising at least one compound of Formula (I) are adapted for administration by inhalation for the treatment of respiratory diseases and/or disorders associated with TIK7 or TIK8 activity. In certain embodiments, the respiratory disease is allergic asthma.

Combined treatment

In some embodiments, compounds of formula (1)-(XMI) described by the authors, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing at least one compound of formula (1)-(XMI) described by the authors, are administered separately (without additional therapeutic agent) for the treatment of one or more diseases and/or disorders associated with the activity of TI K, described by the authors.

In other embodiments, the compounds of formula (1)-(XMI) described by the authors, or their pharmaceutically acceptable salts or solvates, or a pharmaceutical composition containing at least one compound of the formula (I) - (XMI) described by the authors, are administered in combination with one or more additional therapeutic agents, for the treatment of one or more diseases and/or disorders associated with the activity of TI K, described by the authors.

In other embodiments, the compounds of formula (1)-(XMI) described by the authors, or their pharmaceutically acceptable salts or solvates, or a pharmaceutical composition containing at least one compound of the formula (I) - (XMI) described by the authors, is formulated in combination with with one or more additional therapeutic agents and is administered for the treatment of one or more diseases and/or disorders associated with the activity of TI K described by the authors.

The compounds of formulas (I) - (XMI) described by the authors, or their pharmaceutically acceptable salts or solvates, or a pharmaceutical composition containing at least one compound of the formulas (I) - (XMI) described by the authors, are administered sequentially with one or more additional therapeutic agents for the treatment of one or more diseases and/or disorders associated with activity

TICs described by the authors.

In other embodiments, the combined therapies proposed by the authors include the administration of a compound of the formula (1)-(XMI) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a compound of the formula (1I)-(XMI) to administration of one or more additional therapeutic agents for the treatment of one or more diseases and/or disorders associated with the activity of TI K, described by the authors.

In other embodiments, the combination therapy proposed by the authors includes the administration of a compound of formula (1)-(XMI) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a compound of formula (1)-(XMI), after administration of one or more additional therapeutic agents for the treatment of one or more diseases and/or disorders associated with the activity of TI K, described by the authors.

In some embodiments, the combined therapies proposed by the authors include the administration of a compound of formula (1)-(XMI) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a compound of formula (1I)-(XMI), simultaneously with one or more additional therapeutic agents, for the treatment of one or more diseases and/or disorders associated with the activity of TI K, described by the authors.

In some embodiments, the combination therapies proposed by the authors include administration of a compound of formula (1)-(XMI) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of formula (1)-(XMI) formulated with with one or more additional therapeutic agents, for the treatment of one or more diseases and/or disorders associated with the activity of TI K, described by the authors.

In some embodiments of the combination therapies proposed by the authors, the compound of formula (I), or its pharmaceutically acceptable salt or solvate, are modulators of TIC activity. In some embodiments of the combination therapies described by the authors, the compound of formula (I), or its pharmaceutically acceptable salt or solvate, are TI K7 agonists In some embodiments of the combination therapies described by the authors, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is a TI K8 agonist.

In some embodiments of the combination therapies described by the authors, the compounds of formula (Her) described by the authors, or pharmaceutically acceptable salts or solvates thereof, and the additional therapeutic agent(s) act additively. In some embodiments of the combination therapies described by the authors, the compounds of formula (I) described by the authors, or their pharmaceutically acceptable salts or solvates, and an additional therapeutic agent) act synergistically.

In other embodiments, the compounds of formula (I) described by the authors, or their pharmaceutically acceptable salts or solvates, or a pharmaceutical composition containing the compounds of formula (1), are administered to a patient who is not previously or currently undergoing treatment with another therapeutic agent.

Additional therapeutic agents used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, antibiotics or antibacterial agents, antiemetic agents, antifungal agents, anti-inflammatory agents, antiviral agents , immunomodulatory agents, cytokines, antidepressants, hormones, alkylating agents, antimetabolites, antitumor antibiotics, antimitotic agents, topoisomerase inhibitors, cytostatics, antiinvasive agents, antiangiogenic agents, growth factor function inhibitors, viral replication inhibitors, viral enzyme inhibitors, anticancer agents, o- interferons, p-interferons, ribavirin, hormones, cytokines and other modulators of toll-like receptors.

Antibiotics or antibacterial drugs used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, valganciclovir hydrochloride, metronidazole, beta-lactam antibiotics, macrolides (eg, only as an example, azithromycin, tobramycin (TOVI"M)), cephalosporins (eg, as an example only, Cefaclor, Cefadroxil, cephalexin, cCEORadin, cefamandole, cefatrizine, cefazedone, cefixime, cefozopran, cefpimizole, cefuroxime, cefpiramide, cefprozil, cefpirome , Kepyeh"m, MEGOBEBE"M, SEETIM "M, SEBE m, Sesiog"m, Zurgakh M ii

SYOKISEEE M), clarithromycin (for example, only as an example, clarithromycin and VIACHIM"M), erythromycin (for example, only as an example, erythromycin and EMUSIM"M), ciprofloxacin,

SIRKO M, norfloxacin (e.g., by way of example only, MOKOHIM"M), aminoglycoside antibiotics (e.g., by way of example only, apramycin, arbekacin, bambermycins, butyrosin, dibekacin, neomycin, neomycin, boldenone, netilmicin, paromomycin, ribostamycin, sisomycin and spectinomycin), amphenicol antibiotics (e.g., by way of example only, azidamphenicol, chloramphenicol, florphenicol, and thiamphenicol), ansamycin antibiotics (e.g., by way of example only, rifamide and rifampicin), carbacephems (e.g., by way of example only, lorazepam), carbapenems (e.g., by way of example only, biapenem and imipenem), cephamycins (such as, for example, cefbuperazone, cefmetazole, and cefminox), monobactams (e.g., by way of example only, aztreonam, carumone, and tigemon), oxazephems (e.g., only as an example,

flomoxef and moxalactam), penicillins (eg, by way of example only, amdinocillin, amdinocillin pyloxyl, amoxicillin, bacampicillin, benzylpenicillin acid, benzylpenicillin sodium, epicillin, phenbenicillin, floxacillin, penamcillin, penetamate hydroiodide, penicillin O-benethamine, penicillin 0, penicillin M , penicillin M benzathine, penicillin M, hydrabamine, penimepicycline, phenzigicillin potassium, M-SiPip

KM and REM MEE KM), lincosamides (eg, by way of example only, clindamycin and lincomycin), amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, tetracyclines (eg, by way of example only, apicycline, chlortetracycline, clomocycline, and demeclocycline ), 2,4-diaminopyrimidines (e.g., by way of example only, brodimoprim), nitrofurans (such as, for example, furaltadone and furazolium chloride), quinolones and its analogs (e.g., by way of example only, fluoroquinolones, ofloxacin, cinoxacin, clinaflozacin , flumequine, grepaglioxacin and

ESOKHIM"M), sulfonamides (e.g., by way of example only, acetyl sulfamethoxypyrazine, benzyl sulfamide, nopril sulfamide, phthalylsulfacetamide, sulfachryzoidine, and sulfacitin), sulfones (e.g., by way of example only, diathimosulfone, sodium glucosulfone (and solasulfone), cycloserine, mupirocin, tuberine and their combinations.

Antiemetic agents used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, aminazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine , acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, metalthal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron and their combinations.

Antifungal drugs used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, amphotericin B, itraconazole, ketoconazole, fluconazole, fosfluconazole, intrathecal, flucytosine, miconazole, butoconazole, itraconazole, clotrimazole, nystatin, terconazole, tioconazole, voriconazole, ciclopirox, econazole, haloprogrin, naftifine, terbinafine, boldenone, and griseofulvin.

Anti-inflammatory agents used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate , olsalazine, sulfasalazine, paracetamol, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pioxicam, tenoxicam, nabumetom, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide, leukotriene antagonists including but not limited to zileuton, aurothioglucose, sodium gold thiomalate and auranofin, steroids including but not limited to alclomethasone dipropionate, amquinonide , beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, clobetasol propionate, clocortolone pivalate, hydrocortisone, hydrocortisone derivatives, desonide, deoxymethasone, dexamethasone, flunisolide, flucoxinolide, flurandrenolide, galquinokide, medrisone, methylprednisolone, methylprednisolone acetate, methylprednisolone succinate sodium furoate, mozazone . its derivative, 5-aminosalicylic acid, retinoids, dithranol or calcipotriol, sulfinpyrazone and benzbromarone.

Antiviral drugs used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, protease inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside inhibitors reverse transcriptase (NNRTI), SSR1 antagonists,

SSK5 antagonists and nucleoside analogues. Antiviral drugs include, but are not limited to, fomivirsen, didanosine, lamivudine, stavudine, zalcitabine, zidovudine, acyclovir, famciclovir, valacyclovir, ganciclovir, gangciclovir, cidofovir, zanamivir, oseltamavir, vidarabine, idoxuridine, trifluridine, levavirin, viramidine, and ribavirin, and foscarnet, amantadine, rimantadine, saquinavir, indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, P-interferons, p-interferons; adefovir, clevadine, entecavir, pleconaril, NSMU-086, EM2702, emtricitabine, kelgozivir, valopicitabine, NSM protease inhibitors such as VISM 2061, 5СН-503034, ITMM-191 or МУХ-950, M55В polymerase inhibitors such as MM107 ( and its predecessor MM283), K1626, 7078, VIIM1941, o5Kb25433, SI 09128 or NSU-796, Efavirenz, NVU-097, nevirapine, TMO-120 (dapivirine), TMO-125, B-

471. -695634, PMI-150, calanolide, TAK-779, 560-351 125, ancriviroc, vicriviroc, maraviroc, RKO-140, aplaviroc 40, Opo-4128, AK-602), AMO-887 SMRO-167, methyl-1 -endo-(8-(35)-3-"(acetylamino)-3-(3-fluorophenyl)propyl|-8-azabicyclo I3.-2,oct-33-yl)-2-methyl-4,5, 6,7-tetrahydro-1H-imidazo (|4,5-s|Ipyridine-5-carboxylic acid, methyl-3-endo-/8-((35)-3-"(acetamido)- 3-(Z- fluorophenyl) propyl|-8-azabicyclo|3,2.-1|oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-ZN-imidazo|4,5- cIpyridine-5-carbon acid, ethyl-1-endo-(8-((35)-3-(acetylamino)-3-(33-fluorophenyl)propyl|-8-azabicyclo I3.-2,oct-3-yl)-2-methyl -4,5,6,7-tetrahydro-1 H-imidazo |4,5-s|Ipyridine-5-carboxylic acid and

M-C15)-3-3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo|4,-5-c|pyridin-1-yl)-8- azabicyclo!|3.2. C-oct-8-yl|-1-(3-fluorophenyl)propyl)acetamide), BM5-806, BM5-488043, methylamide 5-(15)-2-K2H8)-4-benzoyl-2-methyl-piperazine-1 -yl|-1-methyl-2-oxo-ethoxy)-4-methoxy-pyridin-2-carboxylic acid and 4-15)-2-K2A8)-4-benzoyl-2-methyl-piperazin-1-yl |-1-methyl-2-oxo-ethoxy)-3-methoxy-M-methylbenzamide, enfuvirtide (T-20), zifuvirtide 5P-OT1A, T1249, PO 542, AMO-3100, soluble CO4 inhibitors,

NMO CoA reductase, atorvastatin, 3-0-(3'3'-dimethylsuccinyl)betulinic acid (otherwise known as

RA-457) and 0-NaOA.

Immunomodulatory agents used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, azathioprine, tacrolimus, cyclosporine, methotrexate, leflunomide, corticosteroids, cyclophosphamide, cyclosporine, cyclosporine c, mycophenolate mofetil, ascomycin, rapamycin (sirolimus), EC-506, mizoribine, deoxyspergualine, brequinar, mycophenolic acid, malononitriloamides (e.g., by way of example only, leflunamide), T cell receptor modulators and cytokine receptor modulators, peptidomimetics and antibodies (e.g. , as an example only, human, humanized, chimeric monoclonal, polyclonal, fragments of Em5, ZSEmM5,

Eab or E(ar)2 or epitope-binding fragments), nucleic acid molecules (eg, by way of example only, antisense nucleic acid molecules and triple helices), small molecules, organic compounds and inorganic compounds. Examples of T cell receptor modulators include, but are not limited to, anti-T cell receptor antibodies (e.g., by way of example only, anti-CO4 antibodies (e.g., by way of example only, CM-T412 (Voengipage), IES-CE9 .1 tm (IES and 5KV), tAV 4162UU/94, Opposiope and OKTSag4a (dapzzep-Siiad)), anti-POZ antibodies (for example, only as an example, Mimiop (Rhodisi YuOevzidp Gab5), OKTZ (dopypbop 4 dopp5op), or Rituxan (IES)), anti-CO5 antibodies (e.g., by way of example only, anti-CHO5 ricin-linked immunoconjugate), anti-CO7 antibodies (e.g., by way of example only, SNN-380 (Momagii5) ), anti-

CO8 antibodies, anti-CO40 ligand monoclonal antibodies (e.g., by way of example only, IUES-131 (IES)), anti-CO52 antibodies (e.g., by way of example only, Satrayi 1H (Pekh)), anti-COr2 antibodies, anti -CO11a antibodies (e.g., by way of example only, Hapeyit (cSepepies)), anti-B7 antibodies (e.g., by way of example only, IUOES-114 (IOES)), STI A4-immunoglobulin, and other modulators of OII-like receptors (TIC ). Examples of cytokine receptor modulators include, but are not limited to, soluble cytokine receptors (e.g., by way of example only, the TME receptor extracellular domain or fragment thereof, the receptor extracellular domain 1-18 or a fragment thereof, the receptor extracellular domain 1-6 or a fragment thereof), cytokines or fragments thereof (eg, by way of example only, interleukin (1-2, 1-3, 1-4, 11 -5, 1-6, 11 -7, 1-8, 11 -9, 1 -10,

IS-11, 12-12, 11-15, TME-alpha, interferon (IEM)-a, TEM-D, IEM-y, and ZM-C5E), anti-cytokine receptor antibodies (for example, by way of example only, anti-IEM receptor antibodies, anti-II!-2 receptor antibodies (for example, by way of example only, 2eparach (Rgoivip Oezidp I paragraph)), anti-I!-4 receptor antibodies, anti-II -6 receptor antibodies, anti- IL-10 receptor antibodies, and anti-IL-12 receptor antibodies), anti-cytokine antibodies (eg, by way of example only, anti-IEM antibodies, anti-TME-a

Mantitila, anti-I/-1Df antibodies, anti-II-6 antibodies, anti-II-8 antibodies (eg, by way of example only, AVX-III -8 (Ardepikh)), and anti-II -12 antibodies).

Cytokines or modulators of cytokine function used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, interleukin-2 (I/-2), interleukin-3 ( II -3), interleukin-4 (II -4), interleukin-5 (II -5), interleukin-b (II -6), interleukin-7 (II -7), interleukin-9 (II -9), interleukin-1O0 (11-10), interleukin-12 (1-12), interleukin 15 (11-15), interleukin 18 (1-18), platelet-derived growth factor (ROSE), erythropoietin (ERO), epidermal growth factor ( ESE), fibroblast growth factor (ESE), granulocyte macrophage-stimulating factor (ZM-C5BE), granulocyte colony-stimulating factor (5-C5E), macrophage colony-stimulating factor (M-C5PE), prolactin, alpha-, beta- and gamma-interferon, interferon VD-1a, interferon D-1B, interferon a-1, interferon a-2a (roferon), interferon a-2p, pegylated interferons (only as an example, peginterferon-o-2a, peginterferon-o-2B), int ron, Peg-Intron, Pegasis, consensus interferon (iptegdep), albumin-interferon a and albuferon.

Antidepressants used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, binedalin, caroxazone, citalopram, dimetazan, phencamine, indalpin, indeloxazin hydrochloride, nefopam, nomifenzine ) Deprenyl, cotinine, roliciprin, rolipram, maprotiline, metrolindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptyline oxide, amoxapine, butryptyline, clomipramine, demciptyline, desipramine, dibenzepine, dimethacrine, dothiepin, doxepin, fluazizine, imipramine, imipramine M-oxide, iprindole . lin, quinupramine, tianeptine, trimipramine, adrafinil, benactizine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levofacetoperan, medifoxamine, milnacipran, minaprin, moclobemide, nenfazodone, oxafol piperalin, prolintan, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospiron, tozalinone, tofenacin, toloxatone, tranylcypromine, I-tryptophan, venlafaxine, viloxazine, and zimeldin.

In some embodiments, the antidepressants in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, are MAO inhibitors, including, but not limited to, benmoxin, echinopsidin iodide, etriptamine, iprocloside, iproniazid, isocarboxazid, mebanazine, metphendrazine, moclobamide, nialamide, pargyline, phenelzine, pheniprazine, phenoxypropazine, semihydrazine, safrazine, selegiline, I-Deprenyl, toloxatone, and tranylcypromine.

Hormones used in combination with at least one compound of formula (1) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, luteinizing hormone-releasing hormone (LHRH), growth hormone (GH), growth hormone- releasing hormone, ACTH, somatostatin, somatotropin, somatomedin, parathyroid hormone, hypothalamic releasing factors, insulin, glucagon, enkephalins, vasopressin, calcitonin, heparin, low molecular weight heparins, heparinoid, thymostimulin, synthetic and natural opioids, hormones that stimulate thyroid gland insulin , and endorphins.

Alkylating agents used in combination with at least one compound of formula (1) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, nitrogen mustards, ethyleneimines, methylmelamines, alkylsulfonates, nitrosoureas, carmustine, lomustine, triazenes, melphalan, mechlorethamine, cis-platin, oxaliplatin, carboplatin, cyclophosphane, ifosfamide, melphalan, chlorambucil, hexamethylmelaine, thiotepu, busulfan, carmustine, streptozocin, dacarbazine, and temozolomide.

Antimetabolites used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, cytarabil, gemcitabine, and antifolates such as, by way of example only, fluoropyrimidines (by way of example only , 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea.

Antitumor antibiotics in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, anthracyclines, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin.

Antimitotic agents used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, periwinkle alkaloids (by way of example only, vincristine, vinblastine, vindesine and

Vinorelbine), taxoids (Taxol, paclitaxel and Taxotere as examples only) and polokinase inhibitors.

Topoisomerase inhibitors used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, epipodophyllotoxins, by way of example only, etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin .

Cytostatic agents used in combination with at least one compound of formula (1) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, antiestrogens (e.g., by way of example only, tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., by way of example only, bicalutamide, flutamide, nilitamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., by way of example only, goserelin, leuprorelin, leuprolide, and buserelin), progestogens (e.g., as example only, megestrol acetate), aromatase inhibitors (eg, as an example only, such as anastrozole, letrozole, vorazole, and exemestane) and 5α-reductase inhibitors (eg, as an example only, finasteride).

Anti-invasive agents used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, inhibitors of the c-5gs kinase family (such as, by way of example only, 4-( 6β-chloro-2,3-methylenedioxyanilino)-7-(2-(4-methylpiperazin-yl)ethoxy|-5-tetrahydropyran-4-yloxyquinazoline (A200530) and M-(2-chloro-6-methyl) -2-16-N4-(2-hydroxyethyl)piperazine-yl-yl|---methylpyrimidin-4-ylaminothiazole-5-carboxamide (dasatinib, BM5-354825) ), and metalloproteinase inhibitors (e.g., by way of example only , marimastat, urokinase plasminogen activator receptor function inhibitors and heparanase antibodies).

Antiangiogenic agents used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, those that inhibit the effects of vascular endothelial growth factor such as, by way of example only, anti -vascular endothelial cell growth factor antibody bevacizumab (Avastin "M) and tyrosine kinase inhibitors of the MESE receptor, such as 4-(4-bromo-2-fluoroanilino)-b-methoxy-7-(I-methylpiperidin-4-ylmethoxy)quinazoline. (206474), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (А2О2171), vatalanib (RTK787) and 5|ЦИ 1248 ( sunitinib), linomid and inhibitors of amr3Z integrin function and angiostatin.

Inhibitors of growth factor function used in combination with at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, growth factor antibodies and growth factor receptor antibodies (eg, only as example, anti-ECVV2 antibody trastuzumab (Herceptin'"M), anti-

ESEK antibody panitumumab, anti-EGBVI antibody cetuximab (Egoyikh, C225), tyrosine kinase inhibitors such as, for example, epidermal growth factor family inhibitors (eg, tyrosine kinase inhibitors

ESEC family such as, by way of example only, M-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-orfolinopropoxy)quinazolin-4-amine (gefitinib, 20,839), M-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, 051-774) and b-acrylamide-M-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)- quinazoline-4-amine (CI 1033), egbB2 tyrosine kinase inhibitors such as, but only by way of example, lapatinib, hepatocyte growth factor family inhibitors, platelet growth factor family inhibitors such as imatinib, Gleevec M, serine/threonine kinase inhibitors (eg, in by way of example only, inhibitors of Kaz/Kai signaling, such as farnesyltransferase inhibitors, such as sorafenib (VAM 43-9006)), inhibitors of cell signaling through MEK and/or AKT kinase, inhibitors of the hepatocyte growth factor family, cS-Kii inhibitors, inhibitors of abi kinases, ISE receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example, A2OI 152, РН7З39358, Ух-680, MI m8054,

B763, MP235, MRB29, Ух-528 and АХЗ39459) and inhibitors of cyclin-dependent kinases such as SOC2 and/or

SOCA inhibitors.

In other embodiments, at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with vascular damaging agents such as, by way of example only, combretastatin A4.

In other embodiments, at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with an antisense therapy, such as, by way of example only, IBIZ5 2503, anti-ha5 antisense.

In other embodiments, at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with gene therapy approaches, including, for example, approaches to replace aberrant genes such as aberrant p53 or aberrant

VXAI or BESA2, SOERT (gene-directed enzyme therapy with pro-drugs) approaches, such as those using the enzyme cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and approaches to increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy medicines.

In other embodiments, at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with immunotherapeutic tactics, including, for example, ex-mimo and ip-mmo tactics to enhance the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin-2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, tactics to reduce T-cell anergy, tactics using transfected immune cells, such as cytokine-transfected dendritic cells, tactics using cytokine-transfected tumor cell lines and tactics using anti-idiotypic antibodies.

In other embodiments, at least one compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with other treatment methods, including, but not limited to, surgery and radiation therapy (irradiation, neutron beam therapy, electronic - radiation therapy, proton therapy, brachytherapy and systemic radioactive isotopes).

In some embodiments, the compounds of formula (I) described by the authors, or pharmaceutically acceptable salts and solvates thereof, are administered or formulated in combination with an absorption enhancer, including, but not limited to, sodium glucocholate, sodium caprate, M-lauryl-B-O -maltopyranoside, EDTA, and mixed micelles. In some embodiments, such uptake enhancers target the lymphatic system.

In some embodiments, the additional therapeutic agent(s) used in the combination therapy described by the authors includes, but is not limited to, agents such as tumor necrosis factor (TME-o) inhibitors (such as anti-TME monoclonal antibodies (only as an example

Vetisade, COP-870, and adalimumab) and TME receptor immunoglobulin molecules (by way of example only,

Epgei)); non-selective COX-1/COX-2 cyclooxygenase inhibitors (only as an example, piroxicam, diclofenac, propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolone, such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (for example, meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib, and etoricoxib); glucocorticosteroids, methotrexate, lefunomid; hydroxychloroquine, a-penicillamine, auranofin, or other parenteral or oral gold preparations.

In other embodiments, the combinations described by the authors include combinations of a compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with a leukotriene biosynthesis inhibitor, a 5-lipoxygenase inhibitor (5-I0), or a 5-lipoxygenase-activating antagonist protein (EGAR), such as: zileiton; AVT-761; fenleyton; tepoxalin; ABroy-79175; Arron-85761, M-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as 7epesa 20-2138; compound 588-210 661; a pyridinyl-substituted 2-cyanonaphthalene compound such as

II-739, 010, a 2-cyanoquinoline compound such as I-746, 530, or indole or quinoline compounds such as MK-591,

MK-886 and VAUx1005.

In other embodiments, the combinations described by the authors include combinations of a compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with a leukotriene receptor antagonist (IT B4, I TC4, 104 and I TE4) selected from the group, consisting of phenothiazine-3 in such as I-651, 392; amidine compounds, such as RKU-25019c; benzoxalamines, such as ontazolast; benzenecarboximidamides, such as VII. 284/260; and compounds such as zafirlukast, ablukast, montelukast,

SINGULYAR'"M, pranlukast, verlukast (MK-679), HO-12 525, ro-245913, iralukast (SOR 45715A) and

VAUH7195.

In other embodiments, the combinations described by the authors include combinations of the compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with phosphodiesterase (PDE) inhibitors such as methylxanthanin, including theophylline and euphylline; a selective PDE isoenzyme inhibitor, including a PDE4 inhibitor, including, but not limited to, cilomilast or roflumilast, a PDE40 isoform inhibitor, or a PDE-5 inhibitor.

In other embodiments, the combinations described by the authors include combinations of a compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole , azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine.

In other embodiments, the combinations described by the authors include combinations of a compound of the formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with a gastroprotective histamine type 2 receptor antagonist. In other embodiments, the combinations described by the authors include combinations of a compound of the formula ( I), or its pharmaceutically acceptable salt or solvate, described by the authors, with histamine type 4 receptor antagonists.

In other embodiments, the combinations described by the authors include combinations of the compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with an alpha-1/(alpha-2) adrenoceptor agonist, a vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphthyzine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride, or ethylnorepinephrine hydrochloride.

In other embodiments, the combinations described by the authors include combinations of a compound of the formula (I, described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with an anticholinergic agent, including an antagonist of muscarinic receptors (M1, M2, M3), such as atropine, hyoscine , glycopyrrolate, ipratropium bromide, tiotropium bromide, oxytropium methyl, pirenzepine or telenzepine.

In other embodiments, the combinations described by the authors include combinations of a compound of the formula () described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with beta-adrenoceptors (including beta-receptors of subtypes 1-4), such as isoprenaline, salbutamol, albuterol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.

In other embodiments, the combinations described by the authors include combinations of a compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with chromones such as sodium cromoglycate or sodium nedocromil.

In other variants, the combinations described by the authors include combinations of the compound of formula (1) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with a mimetic of insulin-like growth factor type I (ISB-1Y).

In other embodiments, the combinations described by the authors include combinations of a compound of formula (II) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with glucocorticoids such as flunizolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate. .

In other embodiments, the combinations described by the authors include combinations of a compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with an inhibitor of matrix metalloproteases (MMPs), i.e., such as stromelysins, collagenases and gelatinases, and aggrecanase, especially collagenase-1 (MMP-Y), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12.

In other embodiments, the combinations described by the authors include combinations of a compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with modulators of chemokinin receptor function, such as antagonists of SSKI, SSSK2, SSCK2A, SSCK2B, SSZ, SSK4, SS ,

СссРб, СС, СС8, ССКОУ, СС10 and ССКИ11 (for the С-С family); SCHSKI, SCHSK2, SCHSKZ, SCHSA4 and

СХСН5 (for the С-Х-С family) and СХЗСКИ1 for the С-Х3-0 family.

In other embodiments, the combinations described by the authors include combinations of a compound of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, with immunoglobulins (Id), gamma globulin, an Id drug, or an antagonist or antibody modulating Id function, such as an anti-IDCHE (omalizumab).

Compounds of formula (I) as immune potentiators

In some embodiments, pharmaceutical compositions containing at least one compound of formula (I) described by the authors, or its pharmaceutically acceptable salt or solvate, are immunogenic compositions. In some embodiments, such immunogenic compositions can be used as vaccines. In some embodiments, such vaccines are prophylactic (ie, to prevent infection), while in other embodiments, such vaccines are therapeutic (ie, to treat infection).

In other embodiments, the compound(s) of formula (I) described by the authors, or a pharmaceutically acceptable salt or solvate thereof, are immune potentiators and exert an immunostimulating effect when administered compared to immunogenic formulations that do not contain the compound(s) of formula (I) . In some embodiments, compounds of formula (I) exert an immunostimulatory effect upon administration when included in an immunogenic composition that contains one or more immunoregulatory agents, while in other embodiments, compounds of formula (I) exert an immunostimulatory effect upon administration when included in immunogenic composition without the presence of other immunoregulatory agents.

The immunostimulating effect mentioned by the authors is often an enhancement of the effect of immunogenic compositions. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 10 95 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 20 95 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 30-95% compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 4095 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 5095 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 6095 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 7095 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 8095 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 9095 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent. In some embodiments, the effectiveness of the immunogenic composition is increased by at least 10095 compared to the effect of the immunogenic composition in the absence of an immune potentiating agent.

In some embodiments, the enhancement of the effect of the immunogenic composition is determined by increasing the effectiveness of the immunogenic composition to achieve its protective effect. In some embodiments, this increased efficacy is determined by decreasing the likelihood that a patient receiving the immunogenic composition will have a condition for which the immunogenic composition is considered protective, or by reducing the duration and severity of the effects of such a condition. In other embodiments, this increase in efficacy is measured as an increase in antibody titer induced by the immunogenic composition in the patient being treated.

Together with one or more compounds of formula (I) described by the authors, or their pharmaceutically acceptable salts or solvates, such immunogenic compositions include an effective amount of one or more antigens, and a pharmaceutically acceptable carrier. Such carriers include, but are not limited to, proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, sucrose, trehalose, lactose, lipid aggregates (eg, oil droplets or liposomes), and inactive viral particles. Immunogenic compositions usually also contain solvents such as water, saline, and glycerin, and contain other excipients such as wetting agents or emulsifiers and pH buffering agents.

In some embodiments, immunogenic compositions optionally include one or more immunoregulatory agents. In some embodiments, one or more immunoregulatory agents include one or more adjuvant agents. Such adjuvants include, but are not limited to, TNI adjuvant and/or TN2 adjuvant, discussed below. In some embodiments, adjuvants used in the immunogenic composition provided by the authors include, but are not limited to:

A. Compositions containing minerals;

B. Oil emulsions;

C. Formulation of saponins; p. Virosomes and virus-like particles;

E. Bacterial or microbial derivatives;

E. Human immunomodulators;

C. Bioadhesives and mucoadhesives;

N. Microparticles;

I. Liposomes;

U. Formulation of polyoxyethylene ether and polyoxyethylene ester;

K. Polyphosphazene (RSRR);

I. Muramylpeptides, and

M. Imidazoquinolone compounds.

Mineral-containing compositions suitable for use as adjuvants include, but are not limited to, mineral salts such as aluminum salts and calcium salts. By way of example only, such mineral salts include hydroxides (e.g., hydroxides, including aluminum hydroxides and aluminum oxyhydroxides), phosphates (e.g., hydroxyphosphates and orthophosphates, including aluminum phosphates, aluminum hydroxyphosphates, aluminum orthophosphates, and calcium phosphate) , sulfates (for example, aluminum sulfate), or mixtures of various mineral compounds. Such mineral salts are in any acceptable form, such as, by way of example only, gel, crystalline and amorphous forms. In some embodiments, such mineral-containing compositions are formulated in the form of metal salt particles. In some embodiments, the components of the immunogenic composition described by the authors are adsorbed on such mineral salts. In some embodiments, the adjuvant aluminum hydroxide or aluminum phosphate is used in the immunogenic compositions described in this document. In other embodiments, the antigens used in the immunogenic composition described by the authors are adsorbed on such adjuvant aluminum hydroxide and/or aluminum phosphate. In some embodiments, the adjuvant calcium phosphate is used in the immunogenic compositions described herein. In other embodiments, the antigens used in the immunogenic composition described by the authors are adsorbed on such adjuvant calcium phosphate.

In some embodiments, aluminum phosphates are used as an adjuvant in the immunogenic composition described in this document. In other embodiments, aluminum phosphates are used as an adjuvant in the immunogenic composition described by the authors, where such compositions include the saccharide antigen H. ipPtseplaye. In some embodiments, the adjuvant is amorphous aluminum hydroxyphosphate with a molar ratio of РОЗ/AI from 0.84 to 0.92, included at 0.6 mg

AIz:/ml. In other embodiments, adsorption with a low dose of aluminum phosphate is used, only as an example, from 50 to 100 μg of AIZ" in the conjugate per dose. Where there is more than one conjugate in the composition, not all conjugates must be adsorbed.

Oil emulsions suitable for use as adjuvants include, but are not limited to, squalene-water emulsions (eg, ME59 (5 95 Squalene, 0.5 95 Tween-80, and 0.5 95 brap 85 formulated in submicron particles using a microfluidizer), Freund's adjuvant (CEA) and incomplete Freund's adjuvant (IBA).

Saponins are heterologous groups of sterol glycosides and triterpene glycosides found in the bark, leaves, stems, roots, and even flowers of a wide range of plant species. Saponin compositions suitable for use as adjuvants include, but are not limited to, saponins from the bark of the soap tree OciPaiia zaropagia Moiipa, from Ztiiah ogpaida (zagzarpia),

Surzorpia rapisshagya (bride's veil), and Zaropagia oiisiapaiii5 (soap root). In some embodiments, saponin compositions suitable for use as adjuvants include, but are not limited to, purified compositions including, but not limited to, 057, 0517, 0518, 0521, OH-A, OH-B, and OH -WITH. 20521 is positioned as ZTIMOG OM M. In other embodiments, saponin compositions include formulations of sterols, cholesterol, and lipids, such as unique particles formed by the combination of saponins and cholesterols, known as immunostimulating complexes (IMCs). In some embodiments, the IZSOM also includes a phospholipid, such as phosphatidylethanolamine or phosphatidylcholine. Any known saponin can be used in IZSOM. In some variants, the implementation of the IXSOM includes one or more of the

EYES, SHE and ONS. In other embodiments, IZESOM5 is not necessarily devoid of additional detergents.

Virosomes and viral particles (VP) suitable for use as an adjuvant include, but are not limited to, one or more viral proteins, optionally combined or formulated with phospholipids. Such virosomes and VUs are generally non-pathogenic, non-replicating, and generally do not contain any native viral genome. In some embodiments, viral proteins are obtained recombinantly, while in other embodiments, viral proteins are isolated from whole viruses.

Viral proteins suitable for use in virosomes or HF include, but are not limited to, proteins derived from influenza viruses (eg, HA or MA), hepatitis B virus (eg, as core or capsid proteins), hepatitis E virus, measles, Sindbis virus, rotavirus, foot-and-mouth disease virus, retrovirus, Norwalk virus, human papillomavirus, HIV, RNA phages (such as envelope proteins), cA phage, EC phage, AR205 phage, and Tu (such as the retrotransposon Tu protein ).

Bacterial or microbial derivatives suitable for use as adjuvants include, but are not limited to, bacterial or microbial derivatives such as non-toxic enterobacterial lipopolysaccharide (IP) derivatives, lipid derivatives, immunostimulatory oligonucleotides, and ADP-ribosylated toxins and their detoxified derivatives Such non-toxic GRO derivatives include, but are not limited to, monophosphoryl lipids (MPI) and 3-O-deacylated MPI. (ZamMmRI). instead, it is a mixture of 33-de-O-acylated monophosphoryl lipids with 4, 5 or b-acylated chains. Other non-toxic derivatives of ARB include monophosphoryl lipid mimetics, such as aminoalkylglucosaminide phosphate derivatives (eg, KS-529). Lipid derivatives include, but are not limited to, lipid derivatives from E. soy (for example, OM-174).

Immunostimulating oligonucleotides used as an adjuvant include, but are not limited to, nucleotide sequences containing the Cpo motif (a dinucleotide sequence containing an unmethylated cytosine bound by a phosphate to a guanosine). Such Cp sequences can be double-stranded or single-stranded. In some embodiments, such nucleotide sequences are double-stranded RNA or oligonucleotides containing palindromic or poly(ys) sequences. In other embodiments, Cp includes nucleotide modifications/analogs, such as phosphorothioate modifications.

In some embodiments, the sequence is directed to TI KU, and in some embodiments, the motif ZTSOSTT or TTSSTT. In some embodiments, the Cpo sequence is specific for stimulating a TAM immune response, such as, for example, Cpo-orm, or in other embodiments, the Cpo sequence is more specific for triggering a B-cell response, such as, for example, Cpo-B OM.

In some embodiments, Sro is Sro-A OM.

In some embodiments, Cpo oligonucleotides are constructed so that the 5' end is available for recognition by the receptor. In other embodiments, two Cpo oligonucleotide sequences are optionally attached to the 3' end in the form of "immunomers".

A particularly useful adjuvant based on immunostimulatory oligonucleotides, known as IsC-317mM, In some embodiments, the adjuvant used with the immunogenic compositions described herein includes a mixture of oligonucleotide(s) (eg, only as e.g., 15-40 nucleotides) including at least one (preferably several) Cri motifs (such as, by way of example, cytosine linked to inosine to form a dinucleotide), and (ii) a polycationic polymer, such as, by way of example example, an oligopeptide (for example, only as an example, 5-20 amino acids), including at least one (and preferably several) tripeptide sequence I uz-Agd-G uz. In some embodiments, the oligonucleotide is a deoxynucleotide containing a 26-stranded sequence of 5'-(IS)1z-3. In other embodiments, the polycationic polymer is a peptide containing the 11-membered amino acid sequence KK CI KI K.

In some embodiments, bacterial AOR-ribosylating toxins and their detoxified derivatives are used as an adjuvant in the immunogenic composition described herein. In some embodiments, such proteins are derived from E. soy (E. soy thermolabile enterotoxin "I T"), cholera ("KT"), or pertussis ("PT"). In other embodiments, the toxin or toxoid is in the form of a holotoxin, which includes A- and B-subunits. In other embodiments, the A subunit contains a detoxifying mutation while the B subunit is unmutated. In other embodiments, the adjuvant is a detoxified I T mutant, such as I T-Kb3, I T-K72, and I T-Cs1192.

Human immunomodulators suitable for use as adjuvants include, but are not limited to, cytokines such as, by way of example only, interleukins (1--1, I-2, 1-4, 1-5, 1-6 ,

IS-7, 11-12), interferons (for example, interferon-γ, by way of example only), macrophage colony-stimulating factor and tumor necrosis factor.

Bioadhesives and mucoadhesives used as an adjuvant in the immunogenic composition described by the authors include, but are not limited to, microspheres of esterified hyaluronic acid, and cross-linked derivatives of poly(acrylic acid), polyvinyl alcohol, polyvinylpyrrolidone, polysaccharides, and carboxymethylcellulose. In some embodiments, chitosan and its derivatives are used as an adjuvant in the vaccine compositions described by the authors.

Microparticles suitable for use as an adjuvant include, but are not limited to, microparticles formed from materials that are biocompatible and nontoxic (eg, poly(alpha-hydroxy acids), polyhydroxybutyric acid, polyorthoester, polyanhydride, polycaprolactone, etc.). d.), with poly(lactide-co-glycolide). In some embodiments, such microparticles are considered to have a negatively charged surface (eg, with 505) or a positively charged surface (eg, with a cationic detergent such as STAV). Microparticles suitable for use as an adjuvant have a particle diameter of approximately 100 nm to 150 μm. In some embodiments, the particle diameter is approximately 200 nm to 30 μm, in other embodiments, the particle diameter is approximately 500 nm to 10 μm.

Polyoxyethylene ether and polyoxyethylene ether compositions suitable for use as adjuvants include, but are not limited to, polyoxyethylene sorbitan ether surfactants in combination with octoxynol, and polyoxyethylene alkyl ether or ether surfactants in combination with at least one an additional nonionic surfactant such as octoxynol. In some embodiments, the polyoxyethylene ethers are selected from polyoxyethylene-9-lauryl ether (I ashei 9), polyoxyethylene-9-steoryl ether, polyoxyethylene-8-steoryl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35-lauryl ether and polyoxyethylene- 23-lauryl ether.

Muramyl peptides suitable for use as adjuvants include, but are not limited to, M-acetyl-muramyl-! -threonyl-O-isoglutamine ((Sh-MOP), M-acetyl-normuramyl-I -alanyl-O-isoglutamine (pog-MOP), M-acetylmuramoyl-| -alanyl-O-isoglutaminyl-Y -alanine-2- (1"-2'-dipalmitoyl-5-M-glyceryl-3-hydroxyphosphoryloxy)-ethylamine MTP-PE).

In some embodiments, one or more compounds of formula (I) used as an immune potentiating agent are included in compositions containing combinations of one or more adjuvants specified above. Such combinations include, but are not limited to, (1) saponin and an oil-in-water emulsion; (2) saponin (e.g., 521) and non-toxic derivatives of HAZ (e.g., ZaAMRI); (3) saponin (e.g., 521) and non-toxic derivatives of HAZ (e.g., ЗаМРИ) and cholesterol; (4) saponins (for example, 0521) "3 aMRTI-II -12 (optionally including styrene); (5) ZaMRI combinations, for example, 0521 and/or oil-in-water emulsions; (6) BAK containing 10 95 squalane, 0.4 95 Twin 80.TM., 5 95 pluronium-block-copolymer 1121, and ipg-

MOR, either microfluidized into a submicron emulsion or vortexed to create a larger particle size emulsion. (7) KIVI M adjuvant system (RAS), (KIVI Ittypospet) containing 2 95 squalene, 0.2 905 Tween-80, and one or more bacterial cell wall components from the group consisting of monophosphorylipid A (MR ), trehalose dimycolate (TOM) and cell wall framework (SUU5), mainly

MRI "SUUZ (Oeyoch. TM.) and (8) one or more salts of minerals (for example, aluminum salts) and non-toxic derivatives of I RB5 (such as ZOMRI).

In other embodiments, the adjuvant combinations used in the immunogenic combination proposed by the authors include combinations of TA and Tr2 adjuvants, such as, but only as an example, Cro and alum or resiquimod and alum.

In some embodiments, the immunogenic compositions described by the authors elicit a cellular immune response as well as a humoral immune response. In other embodiments, the immune response causes the formation of long-lasting (for example, neutralizing) antibodies and cellular immunity that quickly responds to the influence of an infectious agent.

Two types of T cells, CO4 and CO8 cells, are generally thought to be necessary for the initiation and/or enhancement of cellular immunity and humoral immunity. CO8 T cells can express the CO8 co-receptor and are commonly referred to as cytotoxic T lymphocytes (CTLs). СО8 T-cells are able to recognize or interact with antigens expressed on MHC class I molecules.

Cp4 T-cells can express CO4 co-receptor and are usually called T-helper cells. C04 T-cells are able to recognize antigenic peptides bound to class II MHC molecules.

When interacting with the class II MHC molecule, CO4 cells can secrete factors such as cytokines.

These secreted cytokines can activate B cells, cytotoxic T cells, macrophages, and other cells involved in the immune response. Helper T cells or CO4 cells can be divided into two functionally different subsets: TNI phenotype and TN2 phenotype, which differ in cytokine and effector functions.

Activated TNI cells increase cellular immunity (including an increase in the production of antigen-specific STIs), and therefore are of particular importance in response to intracellular infections.

Activated TNI cells can secrete one or more 1-2, IEM-u and TME-VD. The TNI immune response can lead to the development of a local inflammatory reaction through the activation of macrophages, MK (natural killer) cells, and CO8 cytotoxic T-cells (STIs). The TNI immune response may also act to enhance the immune response by stimulating the growth of B and T cells with I--12. TNI-stimulated B-cells can secrete Idsg.

Activated TN2 cells increase the production of antibodies and, therefore, are important for the response to extracellular infection. TN2-activated cells can secrete one or more II-4, I-5, I-6 and /- 10. The TN2 immune response can lead to the production of Ids1, IDE, DA and memory B cells for future protection.

An enhanced immune response may include one or more of an enhanced TNI immune response and a T2 immune response.

TNI immune response may include one or more of the increase in STI, increase in one or more cytokines associated with TNI1 immune response (for example, 1-2, IEM-u and TME-D), increase in the level of activated macrophages, increase in MK activity, or increased Idsga production.

Preferably, TNI enhancement of the immune response will include increased production of Idsg.

TNI adjuvants can be used to trigger a TNI immune response. TNI adjuvants usually cause an increase in the level of IdsSga production in relation to antigen immunization without an adjuvant. TNI adjuvants suitable for use in the immunogenic compositions proposed by the authors include, but are not limited to, formulations of saponins, virosomes and virus-like particles, non-toxic derivatives of enterobacterial lipopolysaccharides (I RB), immunostimulating oligonucleotides. In some embodiments, immunostimulating oligonucleotides used as TNI adjuvant in the proposed immunogenic compositions contain a Cpo motif.

The TN2 immune response may include one or more of an increase in the level of one or more cytokines associated with the TN2 immune response (eg, 1-4, I-5, II-6, and II-10), or an increase in the production of Ids1, IDE, IdDA and memory cells B. Predominantly, enhancement of the TNa2 immune response will include an increase in the production of Ids1.

TN2 adjuvants can be used to trigger a TN2 immune response. TN2 adjuvants usually cause an increase in the level of Ids1 production in relation to antigen immunization without an adjuvant. TN2 adjuvants suitable for use in the immunogenic compositions proposed by the authors include, but are not limited to, mineral-containing compositions, oil emulsions, and ADP-ribosylating toxins and their detoxified derivatives. In some embodiments, the mineral-containing compositions used as TN2 adjuvant in the immunogenic compositions provided by the authors are aluminum salts.

In some embodiments, the immunogenic compositions proposed by the authors include TN1 adjuvant and TN2 adjuvant. In other embodiments, such compositions cause increased TNI and increased TNA response, such as increased production of Yds1 and production of Ydsg2a in relation to immunization without adjuvant. In other embodiments, such compositions containing combinations of TN1 and TN2 adjuvants cause an increase in TN and/or an increase in TN2 immune response relative to immunization with a single adjuvant (ie, relative to immunization with TNI adjuvant subunit or immunization with TN2 adjuvant juvant subunit).

In some embodiments, the immune response is one or both of the TNI immune response and the T2 response. In other embodiments, the immune response involves one or both of an enhanced TNI1 response and an enhanced TNAI response.

In some embodiments, the enhancement of the immune response is one or both of systemic and mucosal immune responses. In other embodiments, the immune response involves one or both of enhanced systemic and enhanced mucosal immune responses. In some embodiments, the mucosal immune response is a TIN2 immune response. In some embodiments, the mucosal immune response includes increased IdA production.

In some embodiments, the immunogenic compositions proposed by the authors are used as vaccines, and such compositions include an immunologically effective amount of one or more antigens).

Antigens for use in the immunogenic composition proposed by the authors include, but are not limited to, one or more of the following antigens listed below, or antigens derived from one or more pathogens listed below.

Bacterial antigens

Bacterial antigens suitable for use in the immunogenic compositions proposed by the authors include, but are not limited to, proteins, polysaccharides, lipopolysaccharides, and outer membrane vesicles that are isolated, purified, or derived from bacteria. In some embodiments, the bacterial antigens include bacterial lysates and formulations from inactivated bacteria. In some embodiments, bacterial antigens are produced by recombinant expression. In some embodiments, bacterial antigens include epitopes that are displayed on the surface of bacteria during at least one stage of its life cycle. Bacterial antigens are mostly conserved among several serotypes. In some embodiments, bacterial antigens include antigens derived from one or more of the bacteria set forth below, and specific examples of the antigens listed below:

Meipzegia tepipoiiae: Mepipoiiae5 antigens include, but are not limited to, proteins, sugars (including polysaccharide, oligosaccharide, lipooligosaccharide, or lipopolysaccharide), or outer membrane vesicles purified or obtained from M. tepipoiidev serogroups such as A, C, MM135, Y, X and/or

A. In some embodiments, the antigens of the protein tepipoide5 are selected from adhesions, Avtovoza, toxins,

It is the acquisition of proteins, membranes and proteins associated with (preferably an integral protein of the outer membrane). zperiososys rpeitopiae: 5bigeriosossiv rpestopiaie antigens include, but are not limited to, saccharides (including polysaccharide or oligosaccharides) and/or proteins from bigeriosossiv rpeitopiae. The saccharide may be a polysaccharide of the size that results from the purification of a monosaccharide from bacteria, or it may be achieved by fragmenting the oligosaccharides of such polysaccharides. In the 7-valent product Rhemupag"M, for example, 6 saccharides are presented as intact polysaccharides, and one (18C serotype) is presented as an oligosaccharide. In some embodiments, the saccharide antigens are selected from one or more of the following pneumococcal serotypes 1, 2, 3, 4, 5, A, 6B, 7E, 8, 9M, 9M, 10A, 11A, 12E, 14, 158, 17E, 18C, 194A, 19BE, 20, 22E, 23 and/or ZZR. The immunogenic composition may include several serotypes eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or more serotypes. 7 -valent, 9-valent, 10-valent, 11-valent and 13-valent conjugate combinations are already known in the art, as is the 23-valent non-conjugate combination. For example, the 10-valent combination may include monosaccharides from serotypes 1 . 22E; 19A and 22E; b A and 158; 19A and 158; g 22E and 158), the 13-valent combination can add to the 11-valent mixture: serotypes 19A and 22E; 81 and 12E; 81158; 81 19A, 8 and 22E; 12E and 158; 12E and 19A; 12E and 22E; 158 and 19A; 158 and 22. etc. In some embodiments, the protein antigens may be selected from the protein defined in US Pat. No. 98/18931, US Pat. No. 98/18930, US Pat.

MO97/37026, MO 02/079241, MO 02/34773, MO 00/06737, MO 00/06738, MO 00/58475, MO 2003/082183, MO 00/37105, MO 02/22167, MO 02/22168, MO 2003/104272, MO 02/08426, MO 01/12219,

MO 99/53940, MO 01/81380, MO 2004/092209, MO 00/76540, MO 2007/116322, I eMivykh ei ai., Iptesi.

Etc. (2006) 74:2453-2456, NovkKipz ei ai., u. Wasietioi!. (2001) 183:5709-5717, Adatoi ei ai., Iptesi. Etc. (2001) 69(2):949-958, Vyyez eyi ai., u. Iptesi beat (2000) 182:1694-1701, TaiKipdyup essays a!., Mr. Rainpod (1996) 21(1):117-22, Veine ei aiI., REEM5 Misgobio!. And hey. (2001) 205(1):99-104, Vhom/p ei ai., Iptesi. Etc. (2001) 69:6702-6706, UUnaiep ei aI., REM5 Ittipoi. Mea. Misgobio!. (2005) 43:73-80, dotaa eyi a!., Massipe (2006) 24(24):5133-5139. In other embodiments, the Zigeriosossi5 rpeshtopiae protein can be selected from the family of Polyhistidine triads (PPH), the family of Choline-binding proteins (SbBrx), cSrXX truncated forms, GUiX family, GuiX truncated forms, chimeric proteins of SBrX-truncated forms and Ux truncated forms forms, pneumolysin (RIu), RZRA, RBAA, 5ri28, ЗРрИОИ, Zrizo, 5ri25, 5riZz3, subunits of rpeitosossai riish5. zigeriosossi5 ruodepe5 (group A streptococcus) group A streptococcus antigens include, but are not limited to, the proteins defined in MO 02/34771 or M/O 2005/032582 (including CA5 40), fusion fragments of ZAZ M proteins (including those described in IMO 02/094851, and Oaie, Massipe (1999) 17:193-200, and Oaie, Massipe 14(10): 944-948), fibronectin protein (5101), streptococcal heme-related protein (ZNR), and streptolysin 5 (Zada).

Mogaheilia antigens: Mogaheilia antigens include, but are not limited to, antigens defined in MO 02/18595 and UMO 99/58562, outer membrane protein antigens (MMPU-OMR), C-antigen, and/or

And RB.

Examples: Pertussis antigens include, but are not limited to, pertussis holotoxin (PT) and filamentous hemagglutinin (ENA) from B. regia55i5, possibly also in combination with pertactin and/or agglutinogens 2 and 3.

Vigkpoidegia: Vigkpoidegia antigens include, but are not limited to, Vigkpoidegia and

Vykpoidegia rzeidotaiyei and VygiKpoiYidegia serasia. Antibiotics: Antigens of Staphylococcus aureus include, but are not limited to, polysaccharides and/or proteins from Antibiotics. Biarnuiosossiv azgeiv polysaccharides include, but are not limited to, capsular polysaccharides of type 5 and type 8 (CRP and CRV), optionally associated with non-toxic recombinant Pseudomonas aeruginosa exotoxin, such as EharpmaX "M, polysaccharides of type 336 (336P5), polysaccharide of intercellular adhesions (RIA, also known as

RMAS). Proteins of 5iarpuiosossiv acgteib, include, but are not limited to, antigens derived from surface proteins, invasins (leukocidin, kinases, hyaluronidase), surface factors that inhibit phagocytic capture (capsule, proteins), carotenoids, catalase production, protein, coagulase, factor blood coagulation and/or toxins for membrane damage (optionally neutralized) that lysis of eukaryotic cell membranes (hemolysins, leukotoxin, leukocidin). In some embodiments, the antigens of biarpuiosossiv ashteiv can be selected from the protein defined in UMO 02/094868, UHO 2008/019162, MO 02/059148, MO 02/102829, MO 03/011899, MO 2005/079315, MO 02/077183, MO 99/27109, MO 01/70955, MO 00/12689, MO 00/12131, MO 2006/032475, MO 2006/032472, MO 2006/032500, MO 2007/113222, MO 2007/1132203, MO 147/1. In other embodiments, antigens of ebarpuiosossiv ashgeiv can be selected from IzaA, Izav, Izas, zag, zago, zagE, SMA, SIV, zaz, ZazbO, ZavzN (AizA), bra, EzasS, EvkhA, EzhB, Etr, Niansbi, SRO, SR8, RMAS, ZZ36RB. Erydeptosis Erydeptosis: Erydeptosis Erydeptosis antigens include, but are not limited to, mucus antigen (ZAA).

Tetanus (Tetanus): Tetanus antigens include, but are not limited to, tetanus toxoid (TT). In some embodiments, such antigens are used as a carrier protein combined/conjugated with the proposed immunogenic compositions.

Siozygidiitis regihipdep5: antigens include, but are not limited to, Epsilon toxin from

Sioziait repgtipdep.

Siozygidiitis Boishpit"5 (botulism): botulism antigens include, but are not limited to, those derived from S. roishipit.

Diphtheria antigens include, but are not limited to, diphtheria toxin, preferably detoxified, such as SCM'97. In addition, antigens capable of modulating, inhibiting, or binding to AUR ribosylation are intended for combination/co-administration/conjugation with the immunogenic compositions proposed by the authors. In some embodiments, diphtheria toxoid is used as carrier proteins.

Naetornishz5 ip'Pshepgaye B (NirB): Nib antigens include, but are not limited to, the monosaccharide antigen Nib.

Reepdotopase aegidipozwa: Rzeidotopase 5x antigens include, but are not limited to, endotoxin, UM77 protein, R. aegidiposa RHZ, RHZ isolated from RAOI (serotype O5), and/or outer membrane proteins, including outer membrane protein E (OrgB).

And ediopePa rpeitorpiia. Bacterial antigens obtained from Hediopepa rpeshtorpia.

SohieiIa Bigpeiiii. Bacterial antigens obtained from Sochiea rigpeii.

Vgyseia. Bacterial antigens obtained from Brucella, including, but not limited to, V. aropyv,

V. sapi, V. teijepbvi5, V. peoiotae, V. omi5, V. 5tsi5 and V. rippirediae.

Egapsipa. Bacterial antigens derived from Egapsipa, including, but not limited to, NO. Pomisida, RE. rpPyotigadia and R. Ishagepviv. zigeriosossi5 adaiasntsae (Zigeriosossi5 group B): antigens of Bigeriossiossi5 group B include, but are not limited to, the protein or saccharide antigen defined in UMO 02/34771, UMO 03/093306, UMO 04/041157, or UMO 2005/002619 (including proteins OV5 80, 85 104, 276 and OV5 685 322, including saccharide antigens obtained from serotypes Ia, IB, Ta/s, II, PI, IM, M, MI, MI and MPP).

Meisetia dopotpoeae: gonorrhea antigens include, but are not limited to, a Rog (or porin) protein such as Rog (see 2pi ei ai!., Massipe (2004) 22:660-669), a transfer binding protein such as

TOR and TrrB (see Rgise et al., Ipiesyop apa Ittipyu (2004) 71(1)x277-283), opacity protein (eg, ORA), reconstituted-modified protein (Cyprus), and preparations of outer membrane vesicles (EMVs). (see Riap'ie ei ai, U Iptesoi5 Oizease (2000) 182:848-855), also see, for example, UUO99/24578,

MO99/36544, MO099/57280, MO02/079243).

Antigens of Antigens: Antigens of Antigens include, but are not limited to, antigens derived from serotypes A, B, Ba, and C (agents of trachoma, causes of blindness), serotypes Y:,1285 13 (associated with lymphogranuloma venereum), and serotypes OK. In some embodiments, antigens

The antigens defined in UMO 00/37494 include, but are not limited to,

UMO 03/049762, UMO 03/068811, or MO 05/002619, including RerA (STO045), I stE (STO89), Ap) (ST381), Opak (ST396), ST398, OtrH-like (ST242), 17112 (ST316), OtsA (ST444), Aio55 (St467), ST547, Epo (ST587), NPA (ST823), and Mygo (ST761).

Tgeropeta radiitis (syphilis): Syphilis antigens include, but are not limited to, antigen

TtrA.

The most common dysgeusia (causing chancroid): the antigens of dysgeusia include, but are not limited to, outer membrane proteins (O5gA).

Epiegosossis Taesaiih or Epiegosossiv Taesisht: antigens include, but are not limited to, trisaccharide repeats or other antigens derived from Epiegosossiv5.

Antigens of Ruiogi: Antigens of H Ruiogi include, but are not limited to, antigens Sad, Mas,

Mar, NoruX, Noru and/or urease.

egiharpuiosossiye zargorpuisisye: antigens include, but are not limited to, the 160-kDa hemagglutinin antigen of C. zargorpuisisiv5.

Uegzipia epiegosoiiisa Antigens include, but are not limited to, I R.

E. soya: E. soya antigens can be obtained from enterotoxigenic E. soya (ETES), enteroaggregative E. soya (EAYAOOES), diffuse-adherent E. soya (AES), enteropathogenic E. soya (ERES), extraintestinal pathogenic E. soya. soybean (EHRES) and/or enterohemorrhagic E. soy (ENES). EHRES antigens include, but are not limited to, auxiliary colonization factor (ogi3526), ogp353, bacterial Id-like domains (group 1) protein (01405), or ogi1364, Moat family of outer membrane-lipoprotein factor ending Tgapzrogpeg (ogi1767), d5rK ( ogi3515), d5ru) (ogp3516), TopB-dependent siderophore receptors (013597), fimbrial protein (03613), ires-948, ires-1232, precursor chains of type 1 fimbrial protein (ires-1875), PEA H homologue (ires -2820), and hemolysins (KESR-3768).

Anthrax: B. apigasis antigens include, but are not limited to, the A component (lethal factor (IEE) and edema factor (EER)), both of which can exchange common B component known as protective antigen (RA) . In some embodiments, antigens of B. apiphagasi5 are optionally detoxified.

Uegzipia rewiese (plague): Plague antigens include, but are not limited to, capsular antigen

E1, GR, antigen M Meghipia Reziiv.

Musobasiegisht ishregscio5ie: TB antigens include, but are not limited to, lipoproteins, GR5, BCG antigens, antigen 858 (A9858) fusion protein, EBAT-6b, additionally formulated in cationic lipid vesicles, isocitrate dehydrogenase Musobasiegisht hyregscio5i5 (MIV) antigens, and MRT51 antigens.

Kiscainvia: Antigens include, but are not limited to, outer membrane proteins, including outer membrane protein A and/or B (OtrB), IRB, and surface protein antigen (5RA).

Meyepia toposuiodepevz: bacterial antigens include, but are not limited to, those derived from

Iivieia toposuiodepev.

Antigens include, but are not limited to, those defined in UMO o2/02606.

Myrgio spoiegae: Antigens include, but are not limited to, proteinase antigens, I RB, in particular Myrgio spoiegae II lipopolysaccharides, O1 Inaba O-specific polysaccharides, 0139 Myrgio spoiegae, IEM108 vaccine antigens, and 2 opium ossitsepzv toxin (270.

ZaItopeiia iurpi (typhoid): antigens include, but are not limited to the above, capsular polysaccharides mainly conjugates (Mi, ie MAX-TUMIi).

Vogtgeiia Biggegegegi (Lyme disease): Antigens include, but are not limited to, lipoproteins (such as O5pA, O5pB, O5R C and O O5p), other surface proteins such as O5pE-related proteins (Egr5), decorin-binding proteins (for example, OBrA), and antigenically variable MI proteins, such as antigens related to RZ39 and P13 (integral membrane protein, MIBE antigenic variable protein.

R. diphtheria: Antigens include, but are not limited to, R. diphtheria outer membrane protein (OMP).

KiIerziea: Antigens include, but are not limited to, OMR, including OMR, or polysaccharide, optionally conjugated to tetanus.

Other bacterial antigens used in the immunogenic compositions proposed by the authors include, but are not limited to, capsular antigens, polysaccharide antigens, or protein antigens of any of the above. Other bacterial antigens used in the immunogenic compositions proposed by the authors include, but are not limited to, preparations of vesicles of the outer membrane (OMM). In addition, other bacterial antigens used in the immunogenic compositions proposed by the authors include, but are not limited to, live, attenuated and/or purified versions of any of the above bacteria. In some embodiments, the bacterial antigens used in the immunogenic compositions proposed by the authors are derived from gram-negative bacteria, while in other embodiments, they are derived from gram-positive bacteria. In some embodiments, the bacterial antigens used in the immunogenic compositions provided by the authors are derived from aerobic bacteria, while in other embodiments, they are derived from anaerobic bacteria.

In some embodiments, any of the bacterial saccharides described above (polysaccharides,

IGR5, VOC or oligosaccharides) interacts with another agent or antigen, for example, a carrier protein (for example, CEM:1o7). In some embodiments, such conjugations are direct conjugations carried out by reductive amination of carbonyl fragments on monosaccharides to amino groups on proteins. In other embodiments, the saccharides are linked through a linker such as succinamide or other linkages presented in Viosopitsdaie Tespidnev, 1996 apa SVS, Spetivigu oi Rgoivip Sopindayop apa Stgovv-HipKipo, 1993.

In some embodiments useful for the treatment or prevention of Mei55egia infection and related diseases and disorders, recombinant proteins from N. tepipoiidia for use in the immunogenic compositions proposed by the authors can be found in MU/099/24578,

МО99/36544, МО099/57280, ММО00/22430, М/О96/29412, МО001/64920, М003/020756, УХО2004/048404, and

UMO2004/032958. Such antigens can be used alone or in combination. When combining multiple purified proteins, it is useful to use a mixture of 10 or fewer (eg, 9, 8, 7, 6, 5, 4, 3, 2) purified antigens.

Particularly useful combinations of antigens for use in the immunogenic compositions provided herein are presented in Sections 1 and 2. (2006) Rhos May Asai si 0 5 A 103(29):10834-9 and

UMO2004/032958, and such an immunogenic composition may include 1, 2, 3, 4 or 5 of: (1) protein "MadA" (aka OMA1994 and MMV1994), (2) protein "NVR" (aka "741" , H P2086, SMA1870, and MMV1870), (3) protein "936 (aka OMA2091 and MMV2091); (4) protein'953" (aka OMA1030 and MMV1030) and (5) protein "287" (aka OMA2132 and MMV2132). Other possible combinations of antigens may include transferrin-binding protein (eg, TOR and/or ТрВ) and H5BE antigen.

Other possible purified antigens for use in immunogenic compositions envisioned by the authors include proteins with one of the following amino acid sequences: 5EO IU MO: 650 z

UO99/24578; BO IO MO: 878 with UM/O99/24578; 5BO IU MO: 884 from UMO99/24578; 5EBEO IYUO MO. 4 with

UMUO099/36544; 5EBO IO MO:598 from UMO99/57280; 5BO IYUO MO: 818 with M/O99/57280; 5EBO IO MO: 864 z

UMO99/57280; 5EO and MO:866 with UUO99/57280; 5EO IYUO MO:1196 with MUO99/57280; 5EO IU MO: 1272 Z

MUO099/57280; 5EO IU MO: 1274 from UMO99/57280; 5BO IU MO:1640 from UMO99/57280; 5EO IYUO MO: 1788 z

MUO099/57280; 5EO IYUO MO: 2288 from UMO99/57280; 5EO and MO: 2466 from UUO99/57280; 5EO IU MO: 2554 z

UMO99/57280; 5EO IU MO: 2576 from UMO99/57280; 5BEO IU MO: 2606 with M/O99/57280; 5EO IYU MO:2608 z

MUO099/57280; 5EO IU MO:2616 with M/O99/57280; BO IU MO: 2668 from UMO99/57280; 5EBO IYUO MO: 2780 z

MUO099/57280; 5EO IO MO: 2932 with MO99 / 57280; 5EO IU MO: 2958 from ММО99/57280; 5EO IYUO MO: 2970 z

MO099/57280; 5BO 10 MO: 2988 of UMO99/57280 (each of the above amino acid sequences is incorporated by reference in the cited document), or a polypeptide comprising an amino acid sequence that: (a) has 50 95 or greater identity (e.g., 60 95, 70 Fo , 80 9, 90 96, 95 95, 9995 or more) to the specified sequences and/or (p) consists of fragments of at least n consecutive amino acids from the specified sequences, where n represents 7 or more (for example, 8, 10, 12 , 14, 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 or more).

Popular fragments for (B) include epitopes from the corresponding sequences. More than one (for example, 2, 3, 4, 5, 6) of these polypeptides can be included in immunogenic compositions.

The INVR antigen falls into three different variants (ММО2004/048404). A vaccine of serogroup N. tetipoiiadev based on the immunogenic compositions described by the authors, using one of the compounds described by the authors, may include one INVR variant, but it will be useful to include INVR from each of two or all three variants. Thus, the immunogenic composition may include a combination of two or three different purified HVRs selected from: (a) a first protein that contains an amino acid sequence that has at least either sequence identity to ZEBEO IU MO:1 and/or includes an amino acid sequence, consisting of a fragment of at least x adjacent amino acids from BEO IU MO:1; (B) a second protein comprising an amino acid sequence having at least 95% sequence identity to ZEO IU MO: 2 and/or comprising an amino acid sequence consisting of fragments, at least in adjacent amino acids from BEO IU MO 2, and / or (c) a third protein comprising an amino acid sequence having at least c9o sequence identity to 5EO IU MO:Z and/or including an amino acid sequence consisting of fragments of at least 7 contiguous amino acids from BEO IU MO:3.

ZEOIIUO MO: 1

MALA APA TARY ONKOKOGSBSTI o seUVeKMEK KG AASOSABKTUSMOOe M OK KMU EORINSTEMIO

SOT EZSERSOMYKO VNOI TABTESTO VEN SKMUAKNOENISTASENTZEOKIRESSKAT US TAESVOpA,

BOXES RAAKOSMOKIEN CREAM ADALIKROSKENAMIVS M UMOAEKOVUVI OTEOKASEMASVAEMK

TEMOSIVNIST LAKY

ZEOIU MO: 2

MAAPISASI APA TARY ONKOKO OB TI OS eVKMEKI KI AASSAEKTUSMOSO I MTK KMOKUYEVEORVSTEMO

OST EBSERO! UKOrnoAMMAI SIEKICHMRO KIS ICHOVOGI Me EZENTAYEMO ROSKAEUNOoKAreVOpaSOok

IT UTIOEAAKOSNOKIENI KTRESIMUEI AAABY KAPEKONAMI SOT KOBEEKOTUNI AG EOOBASEASBATUKISE

EMNEISIASKIY

ZEOIIUO MO: Z

MAALISTIZI APA TARY ONKOKOI KOT EOR SIMOTST BASIOAEKTEKASOKOMOI MTOKKM OKIZKEORMSKE rost TABORI UKOMN most AGOIEKIMMeoOKtTOoVO MOV BE MO eSENTAYEMOI RIZSKAEUNOKABBBOOR

MORI NUBIPETKKOIA is USVIENIKTI EOMUE AAAEI KALEKUNAMI ZOTE UZEEXT UNI AG ESOBAOBIAVVATUK

ISEKUNE SIASKO.,

Values of a are at least 85, for example, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or more. The p values are at least 85, for example, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or more. Values of c are at least 85, for example, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or more. The values of a, b and c are fundamentally unrelated to each other.

The values of x are at least 7, for example, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 225, 250).

The values of y are at least 7, for example, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 225, 250).

The values of 7 are at least 7, for example 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 225, 250).

The values of x, y and 7 are fundamentally unrelated to each other.

In some embodiments, the immunogenic compositions described by the authors will include INVR protein(s) that are lipidated, for example, at the M-terminal cysteine. In other embodiments, they will not be lipidated.

Useful immunogenic compositions described by the authors include purified proteins consisting of a mixture of: (I) the first polypeptide from the amino acid sequence "EO IU MO: 4 (II) the second polypeptide from the amino acid sequence 5EЯUO IU MO:5; and (II) a third polypeptide from the amino acid sequence

ZEO IOJU MO:6. See Sishiapi yei ai. (2006) Rgos Mai! Asai 5si 0 5 A 103(29):10834-9 and MO2004/032958.

Useful immunogenic compositions described by the authors include purified proteins, consisting of a mixture of: (I) a first polypeptide having at least ado sequence identity to the amino acid sequence "EC IU MO: 4 (II) a second polypeptide having at least B9o identity sequences to the amino acid sequence of EC IJU MO: 5; and (I) a third polypeptide having at least c 95 sequence identity to the amino acid sequence of ZEO IU MO:6.

ZEOIU MO: 4

MABROMKOASTI 5KRAAREUSEKETEAKEPAR OS YOU saSARVASSSSOMAAUEEMTOMSSIAATOKREMEOE vBASMOMROMAASTOTRUNTRAEMMRASMMMEMOARPASEZEORAMOIROMAMTAS MOasOp RUASSEMASMTA, dastchaAEMMCHOTASVOMRABOTMeBATMesOOgsVTM mm imOosREOMI TI TNoKOReSeOM MR OEEM

EEKI ZPPalMKeMUKKOSKMOosKMOo KA cho MAPS MKO MO and PE eIKRKERTUBANEVVBAVOVV AND RAEMRIRUMOMH

OT MOSEAMOI TONOM ARESMUV UT iZAEKI ROSBUAGEMOSERBKSEMI TAM UMO EM NENTEMSVRBR

ZESVRAAKMOgO Kamo peso I NMT OKEKAAOMOEKOTUMTEM sor maki rASEE MASK VUVRTO

AEKSOROMRASKKESP ss SATUKUPEMUNAMAVEAIYUNEMTe TMM and Te MEersAKA OS KIVITR MAMI. sBSVBONETON KAPI RODASTROTVEMUTKAMEM SKK Mep OMS MN EKTARUKI KABEKEMStOBRMAKTEMS

PORT TKU i m cha MT Ka UVI EAAKO

ZEOIO MO: 5

MUBAMIVAAMZAKVAMUOV TU ZAST OMUMAI BIETTAVBMI VOMMOTk o MORNING NAMES PI ZOMATESEK

ORMSOAVZESAAESUCHUMYUTMAVI RETASPIASO TAKIM TOKMVATI SIBRATODeE AKT TOMU iIMO AND TREEESAO teki tismakmti moms svsvsevmMAAOIVASI APA TARY ONKOKOSG SO TI ROBUMEKI KI AASSAEK teizMmereg MTekmmMokUeeeORIV STEP EBSERUKAVNAIESMUSTAKOPESO

ASENTOROKI RESSRATUVSTARSBOpPASSMKI TUTORAAKOSMOKIENS KREMU AAAPIKROSKENAMSM ESS VU WITH KASEMASVAYEUUTUMOVNISI AAKSY

ZEOIIUO MO: 6

ATMOOPOUKKAAGUAIDAA MO SE MSE KASETUOYI EY STI TEKPATAASMEAL OKO KKUMTMSTETUMEMKO

MUPAKUKAAEZEIEKI TK APTOAAGAITOAAI PATTMASCHKOZEMITTRABETKTMU GUKIPEKI EAMALTUVYKNABAEM

PAS PETMTKAVPEAMUKTAMEAKOITAEETCOMUPAKUKAAETAASKAEAALAASTAMTAAYDKABAMAAKUTPIKATAT

МКОМАКАМОАТУТКЕБОПОКАУНОСИИ МАТТЕКТОТЕ ГГ АБАЕЕКВИАСНОТКОМ ОИ OP КтеЗОИ ЕКЕТКСООИ AgsSAAI

GOD Sam.

Antigens of bacterial vesicles

The immunogenic compositions described by the authors may include outer membrane vesicles. Such outer membrane vesicles can be obtained from a wide range of pathogenic bacteria and used as antigenic components of immunogenic compositions described by the authors.

Vesicles for use as antigenic components of such immunogenic compositions include proteoliposomal vesicles obtained by destroying the bacterial outer membrane in the form of vesicles that include protein components of the outer membrane. Thus, the term includes OMM (sometimes called "bubbles"), microvesicles (MM5, see, for example, M/002/09643), and "native

OMU" (MOMU, see, e.g., Caina! eyii ai. (2002) Iptesi. Ettyp. 70:702-707). The immunogenic compositions described by the authors, which include vesicles from one or more pathogenic bacteria, can be used in the treatment or prevention of infection with such pathogenic bacteria and related diseases and disorders.

Vectors and MOMM are natural membrane vesicles that are formed spontaneously during bacterial growth and released into the culture medium. Vectors can be obtained by culturing bacteria such as Mei5zegia in broth culture medium, separating whole cells with smaller MMs in broth culture medium (eg, by filtration or low-speed centrifugation to pellet only cells and not smaller vesicles), and then collecting MM from cell-depleted media (eg, by filtration, by differential sedimentation or aggregation of MM, high-speed centrifugation to pellet MM). Strains for use in MM production may generally be selected based on the amount of MM produced in the culture (see, for example, US Pat. No. 6,180,111 and UUO01/34642, which describe Meiz5zegia with high MM production).

OMM is obtained artificially from bacteria, and can be obtained using treatment with detergents (eg, deoxycholate) or without detergents (see, for example, UMO04/019977).

Methods of obtaining suitable OMM preparations are well known in this field. Methods for the formation of OMM include the treatment of bacteria with a bile acid salt detergent (for example, salts of lithocholic acid, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, cholic acid, ursocholic acid, etc.) MIRN App. 14(2):67-80) are preferred for treatment of Meyszegia) at a pH high enough not to precipitate the detergent (see, for example, UMO01/91788). Other methods can be performed essentially in the absence of detergent (see, for example, UMO04/019977) using methods such as sonication, homogenization, microfluidization, cavitation, osmotic shock, milling, French press, mixing, etc. Detergent-free or low-detergent methods can retain useful antigens, such as MORA in OMM Meiz5zegia. Thus, the method can use an OMM extraction buffer with 0.595 deoxycholate or less, for example, about 0.2 9, 0.1 U, "0.05 95, or zero.

A useful process for preparing OMM is described in UUO05/004908 and involves ultrafiltration on crude OMU instead of high-speed centrifugation. The process may include an ultracentrifugation step following ultrafiltration.

Vesicles can be obtained from any pathogenic strain, such as M. typhoidea for use with the invention. Vesicles from serogroup V Meizzegpa! typhoid fever can be of any serotype (eg, 1, 2a, 26, 4, 14, 15, 16, etc.), of any serosubtype, and of any immunotype (eg, 11; 12; 13; 13 ,3,7; 110th etc.). Meningococci can be of any appropriate origin, including hyperinvasive and hypervirulent lines, for example, any of the following seven hypervirulent lines: subgroup I; subgroup Ii; MI subgroup 1; ET 5 complex; ET 37 complex; A4 cluster; line 3. These lines were determined by multilocus enzyme electrophoresis (MI EE), but multilocus sequence typing (MI 5T) is also used to classify meningococci, for example, ET 37 complex is 5T 11 complex by MI 5T, ET 5 complex is 51-32 (ET-5), line 3, ZT 41/44, etc. Vesicles can be obtained from strains having one of the following subtypes: P1.2; P1.2.5;

RI1.4; RI1.5; RI1.B5,2; RI.b.s.; RI.Bs, 10; RI1.7,16; RI1.7,166; RI1.7p, 4; RI.9; RI1.15; P1.9,15; P1.12,13; P1.13;

RI1.14; RI1.21,16; P1.22,14.

Vesicles included in the immunogenic compositions described by the authors can be obtained from pathogenic wild-type strains, such as strains of N. tepipuoyiaev5, or from mutant strains. For example, M/O98/56901 discloses preparations of vesicles obtained from M. tepipoiiai»5 with a modified yshig gene. UMO02/09746 teaches that the expression of p5rA should be positively regulated with concomitant exclusion of rogA and sr5. Next, knockout mutants of M. tepipoiidia for the production of OMM were disclosed in МУО02/0974, УМО02/062378, and М/О04/014417.

MUO006/081259 reveals vesicles in which TINVR is positively regulated. Siaazzep ei ai. (1996) 14(10):1001-8 discloses the construction of vesicles from strains modified to express six different subtypes of rogA. A Meizbzepia mutant with a low level of endotoxin, achieved by the exclusion of enzymes involved in the biosynthesis of RB5, can also be used (see, for example,

UMO99/10497 and other documents (2001) and20:6937-6945). All of these and other mutants can be used in the present invention.

Thus, the strains of serogroup B of M. tepipoiidia, included in the immunogenic compositions disclosed by the authors, may in some embodiments express more than one subtype of RogA.

Hexavalent and hexavalent RogA strains were constructed previously. Strains can express 2, 3, 4, 5, 6, 7, 8 and 9 subtypes of RohA: PI1.7,16; P1.5-1,2-2; P1.19,15-1; RI1.5-2.10; RI1.12 1.13;

RI1.7-24; RI.22,14; PI1.7-1,1 and/or P1.18-1,3,6. In other embodiments, the strain may be down-regulated for RogA expression, e.g., in which the amount of RogA has been reduced by at least 20 95 (eg, » 30 95, » 4090, » 50 90, » 60 Zv, » 70 95, 80 90, 90 95, 95 95, etc.), or even excluded, in relation to wild-type levels (for example, in relation to strain H4i4/76, as described in MUMOO3/105890).

In some embodiments, serogroup B strains of M. tepipoyidib5 can overexpress (compared to the corresponding wild-type strain) certain proteins. For example, strains may overexpress M5RA, protein 287 (MMO01/52885 - also referred to as MMV2132 and CMA2132), one or more INVR (M/006/081259 and US Patent Publication 2008/0248065 - also referred to as protein 741,

ММВ1870 and СМА1870), ТрА and/or ТррВ (МУО00/25811), Сy, 2п-superoxide dismutase (МУО00/25811) and others.

In some embodiments, serogroup B strains of M. tepipoiidia may include one or more deletion and/or overexpression mutations. Optimal genes for down-regulation and/or exclusion include: (a) Cp5, SIGA, SIV, Si, SigO, EgrB, szagIE, NigB/M5BV, GrrA, HbBrBv, GrxK, Ora,

Ors, RIIS, RogV, zZiaA, zZiaV, ziaS, Ziar, TrA, and/or TrrV (MUO01/09350); (B) StA, SV, Si, Si,

EefvV, saiIE, NitV/M5BV, GBrA, GBrV, GrhK, Ora, Ors, RioR, RIIS, RtgE, RtgE, 5iaA, 5iaB, 5iasS, 5iab,

ТрА, and/or ТрВ (М/002/09746); (c) ЭхВВ, ЭхРО, птрМ, СИгА, Сив, Сто, саиИЕ, ГРА, ГРБвВ, Ора, Орс,

RIIS, RogV, ziaA, 5iaB, 5iasS, 5iar, TrA, and/or TrV (MUO02/062378); and (94) SIGA, SIV, SIGO, EgrV, OrA,

Or, RIIS, RogV, 5iar, ZupA, ZupV, and/or ZupS (M/O04/014417).

When using a mutant strain in some embodiments, it may have one or more or all of the following characteristics: () negative regulation or exclusion of I diV and/or saIEE for trimming meningococcal I 05; (its) positive regulation of TrPrA; (iii) positive regulation of the National Health Service; (im) positive regulation of OIitr85; (m) positive regulation of HbrA; (mi) positive regulation of M5rA; (mi) exclusion of RogaA; (my) negative regulation or exclusion of EgrV; (their) negative regulation or exclusion of Or; (x) negative regulation or exclusion of Ors; (XII) exhaustion of the gene complex cf. A truncated GO5 may be one that does not include sialyl-lacto-M-neotetraose epitopes, for example, it may be a galactose-deficient IO5. IO5 may not have a chain.

If GO5 is present in the vesicle, then the vesicle can be processed to bind GO5 and protein components ("intravesicle" conjugation (M/004/01 4417)).

The immunogenic compositions described by the authors may include mixtures of vesicles from different strains.

For example, UU003/105890 discloses a vaccine comprising multivalent meningococcal vesicle compositions comprising a first vesicle derived from a meningococcal strain with a serosubtype prevalent in the country of use and a second vesicle derived from a strain that may not have a serosubtype prevalent in the country of use . UUO06/024946 discloses useful combinations of different vesicles. Combinations of vesicles from strains in each of the 12 and 12 immunotypes can be used in some embodiments.

Antigen-based vesicles can be obtained from M. mepipoidea serogroups5 other than serogroup B (for example, M/O01/91788 discloses a process for serogroup A). The immunogenic compositions described by the authors may accordingly include vesicles derived from serogroups other than B (for example, A, C, UMM135 and/or xX) and from bacterial pathogens other than Meizepgia.

Viral antigens

Viral antigens suitable for use in the immunogenic compositions proposed by the authors include, but are not limited to, inactivated (or killed) virus, attenuated virus, cleaved virus compositions, purified subunit compositions, viral proteins that can be isolated, purified, or derived from viruses, virus-like particles (VHP). In some embodiments, viral antigens are obtained from viruses propagated in cell culture or another substrate. In other embodiments, viral antigens are expressed recombinantly. In some embodiments, viral antigens preferably include epitopes that are displayed on the surface of the virus during at least one of the stages of its life cycle. Viral antigens are mostly conserved among several serotypes or isolates.

Viral antigens suitable for use in the immunogenic compositions proposed by the authors include, but are not limited to, antigens derived from one or more of the viruses listed below, as well as examples of specific antigens listed below.

Antigens: viral antigens include, but are not limited to, derived from

Ogpipotuhomig5, such as influenza A, B, and C. In some embodiments, the Ogpipotuhomig5 antigens are selected from one or more viral proteins, including hemagglutinin (HA), neuraminidase (MA), nucleoprotein (MP), protein (MI), membrane protein (M2 ), one or more transcriptase components (RVI, РВ2 and RA). In some embodiments, the viral antigen includes NA and MA. In some embodiments, the influenza antigens are obtained from interpandemic (annual) influenza strains, while in other embodiments, the influenza antigens are obtained from strains capable of causing pandemic outbreaks (ie, influenza strains with a novel hemagglutinin compared to the hemagglutinin in currently circulating strains, or influenza virus strains that are pathogenic in birds and have the potential to be transmitted horizontally in the human population, or influenza virus strains that ARE pathogenic in humans).

Ragatuchomygidae viruses: Viral antigens include, but are not limited to, those derived from Ragatuchomygidae viruses such as Rpeshtomygize5 (K5M), Ragatukhomigyze5 (RIM), Megarpeshtomygize5 and

Measles (measles).

Rpeshitomigiv: Viral antigens include, but are not limited to those derived from Rpeshitomigiv5, such as respiratory syncytial virus (RSV), bovine respiratory syncytial virus, murine pneumonia virus, and turkey rhinotracheitis virus. Preferably, Рпештомиги5 is a COM. In some embodiments, the rpeshtomyg5 antigens are selected from one or more of the following proteins, including fusion surface proteins (P), glycoprotein (C) and small hydrophobic protein (5H), matrix proteins M and M2,

nucleocapsid proteins M, P and GI and non-structural proteins M51 and M52. In other embodiments, the rpeitomygiz antigens include E, b, and M. In some embodiments, the rpeitomygiz5 antigens are also formulated or derived from chimeric viruses, such as, for example, chimeric EZM/RIM viruses that include K5ZMU and RIM components.

Ragatuchomigia: Viral antigens include, but are not limited to, those derived from paramyxoviruses, such as parainfluenza virus types 1-4 (RIM), mumps, Sendai viruses, simian virus 5, bovine parainfluenza virus, Miraimigi5, Nepyramigi5, and Newcastle disease virus. In some embodiments, the paramyxovirus is MMR or mumps. In some embodiments, the paramyxovirus antigens are selected from one or more of the following proteins: hemagglutinin-neuraminidase (NM), PE1 and E2 fusion proteins, nucleoprotein (MP), phosphoprotein (P), large protein (I), and matrix protein (M). . In other embodiments, paramyxovirus proteins include NM, E1, and E2. In some embodiments, paramyxovirus antigens are also formulated or derived from chimeric viruses, such as, by way of example only, chimeric CZM/RIM viruses containing CZM and RIM components. Commercially available mumps vaccines include live attenuated mumps virus, either in monovalent form or in combination with measles and rubella (MMR) vaccines. In other embodiments, the paramyxovirus is Mirapymiga5 or Nepyramiga5, and the antigens are selected from one or more of the following proteins: fusion protein (P), glycoprotein protein (C), matrix protein (M), nucleocapsid protein (M), Large protein (I ) and phosphoprotein (P).

Rochmygidae: Viral antigens include, but are not limited to, those derived from Rochmygidae, such as Mapioia mega, including, but not limited to, Magioia tatsog and Mapioia tipog.

Meiarpeshtomygius: Viral antigens include, but are not limited to, Meiarpeshtomygius5, such as human Theiarpeshtomygius5 (PMRU) and avian Theiarpeshtomygius5 (AMRM). In some embodiments, theiarpesthomyg antigens are selected from one or more of the following proteins, including surface fusion proteins (PE), glycoprotein (b) and small hydrophobic protein (5H), matrix proteins M and M2, nucleocapsid proteins M, P, and G. B in other embodiments, the antigens of Teiarpestomig5 include EC, SI, and M. In some embodiments, antigens of Teiarpestomig5 are also formulated or derived from chimeric viruses.

Motgbiyimigiye: Viral antigens include, but are not limited to those derived from Mogriyimigiy, such as measles. In some embodiments, the MogbiPimigier antigens are selected from one or more of the following proteins: hemagglutinin (H), glycoprotein (c), fusion factor (P), large protein (I), nucleoprotein (MP), polymerase phosphoprotein (P), and matrix ( M). Commercially available measles vaccines include live attenuated measles virus, usually in combination with mumps and rubella (MMR).

Risogpamigiv: Viral antigens include, but are not limited to, those derived from picornaviruses such as Epiegomiguse5, CPpipomiguse5, Neragpamiguse5, Sagaiomiguse5, and Arpipomiguse5. In some embodiments, the antigens are obtained from enteroviruses, while in other embodiments, the enterovirus is

Royomigi5. In other embodiments, antigens are obtained from rhinoviruses. In some embodiments, antigens are formulated into virus-like particles (VPs).

Epiegomygia: Viral antigens include, but are not limited to, those derived from an enterovirus, such as Remyogamy5 types 1, 2, or 3, Coxsackievirus types 1-22 and 24, Coxsackievirus types 1-6, Echovirus (ECNO)) types 1-9, 11-27 and 29-34 and enterovirus 68-71. In some embodiments, the antigens are obtained from enteroviruses, while in other embodiments, the enterovirus is Regiomigs5. In some embodiments, enterovirus antigens are selected from one or more of the following capsid proteins URO, UR,

MP2, MRZ and MP4. Commercially available polio vaccines include inactivated polio vaccine (IPV) and oral polio vaccine (OPV). In some embodiments, antigens are formulated into virus-like particles.

Vipuamigs: Viral antigens include, but are not limited to, those derived from Ohypobipuamigs, such as California encephalitis virus, RpIebromygs5, such as Chili May fever virus, or

Maigomygi5, such as the Crimean-Congo hemorrhagic fever virus.

KPipomig5: Viral antigens include, but are not limited to, those derived from rhinovirus. In some embodiments, the rhinovirus antigens are selected from one or more of the following capsid proteins: MPO, MP1I, MP2, MP2, and MP4. In some embodiments, antigens are formulated into virus-like particles (VPs).

Neragpamigix: Viral antigens include, but are not limited to, those derived from Neragpamigiv5, such as, by way of example only, hepatitis A virus (HAV). Commercially available HAM vaccines include inactivated HAM vaccines.

Todamiga: Viral antigens include, but are not limited to, those derived from Todamiga5, such as Kybimigha5, AIrpamigha5, or Agehimiga5. In some embodiments, the antigens are derived from Kybimigs5, such as, for example, the rubella virus. In some embodiments, antigens (adamygs5 are selected from

ET, E2, EZ8, C, M5P-1, MORO-2, MOP-Z or M5P-4. In some embodiments, the antigens are selected from Ei, E?2, and Ez. Commercially available rubella vaccines include live, cold-adapted virus, usually in combination with mumps and measles vaccines (MMVs).

Niamimigye: Viral antigens include, but are not limited to, those derived from flaviviruses such as tick-borne encephalitis virus (TEV), dengue virus (types 1, 2, C or 4), yellow fever virus, Japanese encephalitis virus, Quazapyg Eogevi Migi virus5, UUezi Mie epserpaiiov migi5, 21. Gotsi5 epserpaiiov, Russian spring-summer encephalitis virus, Romjazzap encephalitis virus. In some embodiments, flavivirus antigens are selected from RIM, M, C, E, M5-1, M5-2, M526, M53, M54a, M54B, and

M55. In some embodiments, flavivirus antigens are selected from RIM, M, and E. Commercially available TVE vaccine includes inactivated viral vaccines. In some embodiments, antigens are formulated into virus-like particles (VPs).

Remygium: Viral antigens include, but are not limited to those derived from Remygium5, such as bovine diarrhea virus (BDMV), classical swine fever (C5EM), or Border disease (BOD).

Neradpamigiv: Viral antigens include, but are not limited to, those derived from Neradpamigiv5, such as hepatitis virus. In some embodiments, Peradpamiga5 antigens are selected from surface antigens (H, M and 5), core antigens (HBc, HBe). Commercially available HVM vaccines include subunit vaccines containing surface antigen 5 protein.

Hepatitis C virus: Viral antigens include, but are not limited to, those derived from hepatitis C virus (HCV). In some embodiments, the HCM antigens are selected from one or more of E1, E2,

ET/E2, M5345 polyprotein, M5 polyprotein 345-core, core, and/or peptides from non-structural sites.

In some embodiments, hepatitis C virus antigens include one or more of the following:

NCM ET or E2 proteins, E1/E2 heterodimer complexes, core proteins and non-structural proteins or fragments of these antigens, in which the non-structural proteins may be optionally modified to remove enzymatic activity, but retain immunogenicity. In some embodiments, antigens are formulated into virus-like particles (VPs).

NAvbaomigiv: Viral antigens include, but are not limited to, those derived from rhabdovirus such as Guzzamigs5 (Rabies virus) and Mesesciomigs5 (MOM). Rhabdovirus antigens can be selected from glycoprotein (b), nucleoprotein (M), large protein (I), non-structural proteins (M5). Commercially available rabies vaccine includes killed virus grown on human diploid cells or rhesus fetal lung cells.

Saiisimigidaye; viral antigens include, but are not limited to, those derived from Saisimigiidae, such as Norwalk virus, and Norwalk-like viruses, such as Nam/aii Migi5 and Zpom/Moishpiap Migi5. In some embodiments, antigens are formulated into virus-like particles (VPs).

Sogopamigiv: Viral antigens include, but are not limited to, those derived from coronavirus,

ZAK5, human respiratory coronavirus, avian infectious bronchitis (AIB), murine hepatitis virus (MUV), and porcine transmissible gastroenteritis virus (TOZEM). In some embodiments, the coronavirus antigens are selected from peak (5), envelope (E), matrix (M), nucleocapsid (M), and glycoprotein hemagglutinin esterase (HE). In some variants, the embodiment of the corona virus is obtained from the BAK5 virus. In some embodiments, the coronavirus antigen is obtained from the BAK5 viral antigen, as described in UMO 04/92360.

Keigomygium: Viral antigens include, but are not limited to, those derived from retroviruses, such as Opsomigy5, I epimygium, or Zritamigy5. In some embodiments, the opsomyg5 antigens are obtained from NTIM-1, NTI U-2, or NTI M-5. In some embodiments, lentivirus antigens are derived from HIV-1 or HIV-2. In some embodiments, the antigens are derived from HIV-1 subtypes (or monophyletic taxa), including, but not limited to, HIV-1 subtypes (or monophyletic taxa), B, C, 0, E, 0, H, U, K , 0. In other embodiments, antigens are obtained from HIV-1 circulating recombinant forms (SERE), including, but not limited to, A/B, A/E, A/6b, A/5/, etc. In in some embodiments, the retrovirus antigens are selected from dad, roi, epu, ah, yai, geh, hem, pei, mii, mry, and mrg. In some embodiments, HIV antigens are selected from dad (p24dad and rob5dad), EMM (or160 and o9p41), roi, yai, pei, hem mra, miniproteins, (preferably P5O5 dad and dr40m deletion). In some embodiments, HIV antigens are obtained from one or more of the following strains: NiIMy, NiIMeeeg, NIMi du,

NIMil, NIMmm, NIM-Tsmg2z5, NIM-Tova, NIM-T5etv2, NIM-Ttui, NIM-Tmu«. In some embodiments, the antigens are derived from endogenous human retroviruses, including, but not limited to, NEKM-K ("old"

NEVU-K and "new" NEKU-K).

Cheomigich: Viral antigens include, but are not limited to, those derived from reoviruses such as

Ogipogeomigi5, Koiamigi5, Ogbrimigih, or SoiNimigi5. In some embodiments, reovirus antigens are selected from structural proteins A1, 2, AZ, Mt, ng, 01, 02, or 03, or non-structural oM5 proteins, НМ5, or 015. In some embodiments, reovirus antigens are obtained from rotavirus. In some embodiments, the rotavirus antigens are selected from MP1, MP2, MPR, MPA (or a cleaved product of UR5 and

MP8), MP1, MPb, M5P3, M5P2, MP7, MZRA or M5P5. In some embodiments, rotavirus antigens include URA (or a split product of MP5 and MP8), and MP7.

Raghmomyg5: Viral antigens include, but are not limited to, those derived from a parvovirus such as Parvovirus B19. In some embodiments, parvovirus antigens are selected from MP-1, Ur-

2, MR-Z, M5-1 and M5-2. In some embodiments, the parvovirus antigen is the MP1 or MP-2 protein capsid. In some embodiments, antigens are formulated into virus-like particles (VPs).

Hepatitis delta virus (DHV): Viral antigens include, but are not limited to, those derived from

NOM, in particular, b-antigen with NOM.

Hepatitis E virus (HEM): Viral antigens include, but are not limited to, those derived from HEM.

Hepatitis B virus (HBV): viral antigens include, but are not limited to, those obtained from us.

Human Herpes Virus: Viral antigens include, but are not limited to, those derived from human herpes virus, such as, by way of example only, herpes simplex virus (HSV), varicella virus (VVV), Epstein-Barr virus (EBV), cytomegalovirus ( CMV), human herpesvirus 6 (HHV), human herpesvirus 7 (HHV7), and human herpesvirus 8 (HHV8). In some embodiments, human herpesvirus antigens are selected from immediate early proteins (c), early proteins (B), and late proteins (y). In some variants of the proteins, the НЗ5М antigens are obtained from the Н5М-1 and Н5МУ-2 strains. In some embodiments, the antigens of NZM are selected from glycoproteins 98, d9C, d90 and OH, hybrid protein (GB), or immune escape proteins (9C, 9E or 9). In some embodiments, MAM antigens are selected from core, nucleocapsid, envelope, or envelope proteins. A live attenuated MAM vaccine is commercially available. In some embodiments of EVM, antigens are selected from early antigen (EA), viral capsid antigen (MCA) and membrane antigen (MA) glycoproteins. In some embodiments, CMV antigens are selected from capsid proteins, envelope glycoproteins (such as B and OH), and envelope proteins. In other embodiments, CMV antigens can be selected from one or more of the following proteins: ррб5, IET, оВ, 90, 9Н, ой, ОМ, ОМ, 90, О-128, 01129, 901130, 01150, 01131, 033, SH 78, 0527, 528, VI 5A, VI 6, VI 10, VI 11, VI 12, VI 13, 011, 012, 014, 015, 016, 017, 018, 019, 0110, 0111, 0114,

Py15a, Sh1 16, 0117, 0118, 01I22A, 0138, 0140, Ogata, 0142, 01116, 01119, 01120, 01121, AI 124, 182, 0i147a, 01148, 01142, 0113, 0114 , 01139, 01133, AI 135,

Shi 148A, 011488, 01 148C, 011480, 0052, 0053, 0056, 0057, 0058, 0059, 0510, 00511, 0512, 00513, 0514, 0514, 0515, 0516, 0051, 515 O5Z4A. CMV antigens can also be fusions of one or more CMV proteins, such as, by way of example only, rrb5LE! (Kear 6th ai., Massipe (2007) 25:7441-7449). In some embodiments, antigens are formulated into virus-like particles (VPs).

Raromamigize5: Antigens include, but are not limited to, those derived from Raromamigize5, such as Rariotamigize5 and RoiYuotamigize5. In some embodiments, papillomaviruses include HPV serotypes 1, 2, 4, 5, 6, 8, 11, 13, 16, 18, 31, 33, 35, 39, 41, 42, A7, 51, 57, 58, 63, and 65. In some embodiments, HPV antigens are obtained from serotypes 6, 11, 16, or 18. In some embodiments, antigens

HPVs are selected from capsid proteins (1) and (12), or E1-E7, or their fusion. In some embodiments, HPV antigens are formulated into virus-like particles (VPs). In some embodiments, viruses

Roiutoamigs5 include VC virus and UK virus. In some embodiments, the Roiotamig5 antigens are selected from UR1, MP2, and MRZ.

Adepomigiz: Antigens include those derived from adenovirus. In some embodiments, adenovirus antigens are derived from adenovirus serotype 36 (Aa-36). In some embodiments, the antigen is obtained from the sequence of the protein or peptide encoding the Aa-36 envelope protein or its fragment (MO 2007/120362).

Next, the antigens, compositions, methods and microbes included in Massipe5, 4? Edayop (Rioikip apa Ogepvivip unit. 2004); Meadis! Misgobioodu 4 Eayop (Mitau ei ai. ed. 2002); Migoiodu, Za Eaiiop (MU.K. UokiiK ey. 1988); Eipaatenpia! Migoiodu, 2p4 Eaiiop (V.M. Riei5 apa O.M. Kpire, ed5. 1991), which are provided in combination with immunogenic compositions provided by the authors.

Fungal antigens

Fungal antigens for use in the immunogenic compositions proposed by the authors include, but are not limited to, those derived from one or more of the fungi listed below.

Fungal antigens are obtained from Yuegtayorpuyeh5, including: Erideptornuipp YaPossyvit,

Mystosrogyt aschydocypi, Mystosrogyt sapiv, Mystosrogyt aivioyit, Mystosrogyt ediipit, Mystosrogyt dursite, Mystosrogyt papit, Hyisporpuyup sopsepigisct, GPisporpuyup ediipit, Tiispornuyup daipae,

Tysporpuyup durzeit, Pisporpuyup teodpipi, Pisporpuyup tepiadhornuiez, Pisporpuyup diipsKeapite,

Tisporpuyup hybgite, Tiisporpuyup 5spoepivipi, Tiispornpuyup iopzygap5, Pisporpuyp metiso5it, T. metisovyt mag. airit, mag. divsoide5, mag. ospgaseit, Tiispornuiop myoiaseit, and/or Tiispornuiup

Tamitotte; and

Fungal pathogens obtained from Azregoii5 Titida5, Azreghaishv Pamiv, Avregoii5 podeg, Avregoii5 podshatp5, Avregdiyi ieteiyv, Avregdiyi5 5udomi, AvregaiShe PShamaish5, Avregdiyi5 diaysiv,

Viaziozspigotuse5 sariatsv, Sapaida airisap5, Sapaida epoiaze, Sapaida igorisai5, Sapaida diabgaia,

Sapaida Kgizvi, Sapaida ragarziovi5, Sapaida z5iePayuidea, Sapaida Kizvi, Sapaida ragaKmuzvi, Sapaida

Inzyapiae, Sapaida rzepydoihorisaii5, Sapaida diyPenptopai, Siadozrogisht saitiopii, Sossidioidev ittiyv,

Viaziotusevs aeptaiiv, Sturiosossiv peoioptap5, Steoiispit siamaisht, Niviyuoriazta sarzshayut,

KiIebzieIa rpeitopiae, Misgozrogidia, Epsernaiyogoop zvrr., beriaia ipivviipayv apa Epiegosui02oop

Biepeivy; She Iez5 sottop age Vgasnpioia 5yr, Misgozrogidisht 5yr., Mozeta 5yr., Rivivyurnoga 5yr.,

Tgaspiriyeivorpoga 5rr., Miiaipta 5rr Ragasossidioidev5 Bgaviyep5vi5, Rpeitosuviiv saiipii, Ruiyishtp ipvidiovit, Riugozrogyt omaie, Zasspagotuse5 segemizaye, Zasspagotusev bBoshiagii, Zasspagotuseviii rotre, Zsedovrogisht ariozregitii, Todepekhorihi, v5isNerogopii

Repisiyisht tagpeyei, Maiazzelia 5yr., Gopsesaviea 5yr., Mapdiyeia 5yr., Zrogoyigih yr., Vazidioroish5 yr.,

Sopidioroish5 5yr., VpPigoriv 5yr., Mysog vrr.

Mopoiippia rr, VNigosiopia 5rr, Raesiotusez 5rr, Riotusez 5rr, and Siadozrogpit z5rr.

In some embodiments, the method of obtaining fungal antigens includes a method in which the solubilized fraction is extracted and separated from the insoluble fraction obtained from fungal cells in which the cell wall has been substantially removed or at least partially removed, which is characterized in that the process includes the following stages: production of live fungal cells, production of fungal cells in which the cell wall has been substantially removed or at least partially removed; disrupting the fungal cell, where the cell wall has been substantially removed or at least partially removed, obtaining the insoluble fraction, and extracting and separating the solubilized fraction and the insoluble fraction.

Protozoan antigens/pathogens

Protozoan antigens/pathogens for use in the immunogenic compositions described by the authors include, but are not limited to, those derived from one or more of the following protozoa:

Epiatoebva Pniziyu|uiysa, Siagaiia Iatbrii, Sguriozrogidicht ragusht, Susiozroga sauaiiapepvih and Tochoriazta.

Plant antigens/pathogens

Plant antigens/pathogens for use in the immunogenic compositions proposed by the authors include, but are not limited to, those obtained from Vysipye sottypes.

TTO Antigens

In some embodiments, the immunogenic compositions proposed by the authors include one or more antigens derived from sexually transmitted diseases (STDs). In some embodiments, such antigens provide prophylaxis for STDs such as chlamydia, genital herpes, hepatitis (eg, HSM), genital warts, gonorrhea, syphilis, and/or chancre. In other embodiments, such antigens provide therapy for STDs such as chlamydia, genital herpes, hepatitis (eg, HSM), genital warts, gonorrhea, syphilis, and/or chancre. Such antigens are obtained from one or more viral or bacterial STDs. In some embodiments, STD viral antigens are derived from HIV, herpes simplex virus (HSV-1 and HSV-2), human papillomavirus (HPV), and hepatitis (HCV). In some embodiments, bacterial antigens

STDs are obtained from Meiizetia dopotpoeae, Spiatuaea mMaspotaeae5, Tteropeta radiida, Naetorniae5 distgeui, E. soii, and 5igeriosossia5 adaiasiae. Examples of specific antigens derived from these pathogens are described above.

Respiratory antigens

In some embodiments, the immunogenic compositions proposed by the authors include one or more antigens derived from a pathogen that causes respiratory diseases. By way of example only, such respiratory antigens are derived from respiratory viruses such as Ogpipotukhomigizev5 (influenza),

Rpeshitomigi5 (KM), Ragatukhomigi5 (RIM), Mogriimigi5 (measles), Todamigi5 (rubella), MAM and Sogopamigi5 (ZAK5). In some embodiments, the respiratory antigens are obtained from bacteria that cause respiratory diseases, such as, by way of example only, Zgeriosossis rpeshtopiae, Rzeeidotopav5 aegidiposa, VogaeeyeiYia repivzvziz, Musobrasiegist Schbregsciovia, Musoriayeta rpeitopiae, Spiatuaia rpeshtopiae, Vasiish5 apiphagasi5, and Mogataheiia5 sai. Examples of specific antigens derived from these pathogens are described above.

Pediatric vaccine antigens

In some embodiments, the immunogenic compositions proposed by the authors include one or more antigens suitable for use in pediatric patients. Pediatric patients are usually under 3 years of age, or under 2 years of age, or under 1 year of age. Children's antigens are administered several times during 6 months, 1, 2 or 3 years. Pediatric antigens are derived from viruses that may target the pediatric population and/or viruses for which the pediatric population is susceptible to infection. Pediatric viral antigens include, but are not limited to, antigens derived from one or more of Ogipotuhomyga5 (influenza), Rpeshtomigya5 (K5M), Ragatuhomigya5 (RIM and mumps),

Mogriymigi5 (measles), Todamigiz (rubella), Epiegomigiz5 (poliomyelitis), NVM, Sogopamigiz (ZAK5) and varicella virus (MAM), Epstein-Barr virus (EBV). Pediatric bacterial antigens include antigens derived from one or more of Bigeriosossiv rpeshytopiae, Meibvzepa tepipoidev, Zpgeriosossiv ruodepez (group A streptococcus), Mogaheia syaItnaiyi5, VogaeiyePa repivzivziv, Tarpuiosossiv igeiv, SioziaiSht ieiapi (tetanus), Sogpupebasiegiaeit Naip'eto afterivyeti, Pnepgae B (NO), Rzepdotopavh aegydiposa, bZigeriosossiv adaiasiae (group B streptococcus), and E. soii. Examples of specific antigens derived from these pathogens are described above.

Antigens suitable for use in elderly or debilitated individuals

In some embodiments, the immunogenic compositions proposed by the authors include one or more antigens suitable for use in elderly or debilitated individuals. Such people may need to be vaccinated more frequently, with higher doses, or with adjuvant formulations to improve their immune response to target antigens. Antigens that are intended for use in elderly or debilitated individuals include antigens derived from one or more of the following pathogens: Meivzegia tepipoide5, Bigheriosossis rpeitopiae, Zigeriosossis ruodepev (Page A 5igeriosossiv), Mogaheiia sayatnaiiv5, Vogaeiveia repivvziv, earpuiosossiv acygei5, eiarpuiosiossiv erideptiv, Siovtidiyt ieiapi (tetanus), Sogpuperasiegisht airpinegiae (diphtheria), Naetorpiishv ipbiieplae B (NIir), Rzepdotopav aegidiposis, I ediopePa rpeshitornpiia, bigeriusossis adaiasiiae (group B streptococcus), Epiegososis Taesai in,

Neiissorasieg ruiogi, Spiatuaia rpeshtopiae, Ogipotuhomigi5 (influenza), Rpeshtomigi5 (CM), Ragatukhomigi5 (RUM and parotitis), Mogbiiymigi5 (measles), Todamigi5 (rubella), Epiegomigi5 (roiio), NVMU, Sogopamigiz5 (ZANV5),

MapseyPa-2o5ieg migi5 (MAM), Epstein-Barr virus (EBUM), cytomegalovirus (CMM). Examples of specific antigens derived from these pathogens are described above.

Antigens suitable for use in adolescent vaccines

In some embodiments, the immunogenic compositions proposed by the authors include one or more antigens suitable for use in adolescent patients. Adolescents need a booster dose of a previously administered pediatric antigen. Pediatric antigens that are suitable for use in adolescents are described above. In addition, adolescents are focused on receiving antigens derived from STD pathogens in order to provide protective or therapeutic immunity before the onset of sexual activity. STD antigens that are suitable for use in adolescents are described above.

Tumor antigens

In some embodiments, the tumor antigen or cancer antigen is used in combination with the immunogenic compositions provided by the authors. In some embodiments, the tumor antigens are peptide-containing tumor antigens, such as a polypeptide tumor antigen or a glycoprotein tumor antigen. In some embodiments, the tumor antigen is a saccharide-containing tumor antigen, such as a glycolipid tumor antigen or a ganglioside tumor antigen. In some embodiments, the tumor antigen is a polynucleotide-containing tumor antigen expressing a polypeptide-containing tumor antigen, for example, a vector RNA construct or a construct

vector DNA, such as plasmid DNA.

Tumor antigens suitable for use in combination with the immunogenic compositions described by the authors encompass a wide range of molecules such as (a) polypeptide-containing tumor antigens, including polypeptides (which may be, for example, 8-20 amino acids in length , although lengths outside this range are common), lipoproteins and glycoproteins, (b) monosaccharide-containing tumor antigens, including polysaccharides, mucin, ganglioside, glycolipids, and glycoproteins, and (c) polynucleotides that express antigenic polypeptides.

In some embodiments, tumor antigens are, for example, (a) full-length molecules associated with cancer cells, (b) homologues and altered forms of the same, including molecules with deleted, added and/or substituted parts, and (c) fragments of the same. In some embodiments, tumor antigens are presented in recombinant form. In some embodiments, tumor antigens include, for example, class I-restricted antigens recognized by CO8 lymphocytes, or class IP-restricted antigens recognized by CO4 lymphocytes.

In some embodiments, tumor antigens include, but are not limited to, (a) testicular cancer antigens, such as MM-E5O-1, 5552, ZORI, as well as polypeptides of the CACE, BACE, CACE, and MACE family, e.g., CACE-1, ACE-2, ACE-1, ACE-2, ACE-3, ACE-4, ACE-5, ACE-6, and

MACE-12 (which can be used, for example, to treat melanoma, lung, head and neck,

NSCLC, breast, gastrointestinal tract, and bladder), (B) mutated antigens, e.g., p5Z3 (associated with various solid tumors, e.g., colon, lung, head and neck cancer), p21/Ka5 (pov associated with, for example, melanoma, pancreatic cancer and colorectal cancer), SOCA (associated with, for example, melanoma), IOM! (associated with e.g. melanoma), caspase-8 (associated e.g. with head and neck cancer), SIA 0205 (associated e.g. with bladder cancer), NHA-A2-K1701, beta Catenin (associated with, for example, melanoma), TSC (associated with, for example, T-cell, non-Hodgkin lymphoma), VSK-abri (associated with, for example, chronic myelogenous leukemia), triose phosphate isomerase, KIA 0205, SOS-27, and

GOGA-BOT, (c) overexpressed antigens, e.g., Galectin 4 (associated, e.g., with colorectal cancer), Galectin 9 (associated, e.g., with Hodgkin's disease), proteinase C (associated, e.g., with chronic myeloid leukemia), M/T 1 (related, for example, to various leukemias), carbonic anhydrase (related, for example, to kidney cancer), aldolase (related, for example, to lung cancer), RKAME (related to associated with, for example, melanoma), NEK-2/pei (associated with, for example, breast, colon, lung, and ovarian cancer), alpha-fetoprotein (associated with, for example, hepatoma), KA (associated with associated with e.g. colorectal cancer), gastrin (e.g. associated with pancreatic and stomach cancer), telomerase catalytic protein, MOS-1

(associated, for example, with breast and ovarian cancer), (3-250 (associated, for example, with kidney cancer), ro5Z (associated, for example, with breast, colon cancer), and carcinoembryonic antigen (associated with, e.g., breast cancer, lung cancer, and gastrointestinal cancers such as colorectal cancer), (4) shared antigens, e.g., melanoma-melanocyte differentiation antigens, such as MAKT-1/Meiap . , such as PAP,

RBA, ROMA, RBN-RI, ROM-RI, ROM-R2 associated, for example, with prostate cancer, (i) immunoglobulin idiotypes (associated, for example, with myeloma and B-cell lymphoma), and ( 9) other tumor antigens, such as polypeptide and saccharide-containing antigens, including (i) glycoproteins such as sialyl Tp and sialyl Hex (associated, for example, with breast cancer and colorectal cancer), as well as various mucins ; glycoproteins associated with a carrier protein (for example, MOS-1 is associated with KIN); (its) lipopolypeptides (for example, MOS-1 bound to a lipid residue), (ii) polysaccharides (for example, Cioro

H synthetic hexasaccharide) that are associated with carrier proteins (for example, with KIN), (im) gangliosides, such as sesm2g, am12, 102, 03 (associated, for example, with brain cancer, lung cancer, melanoma) , which are also associated with carrier proteins (for example, KI-H).

In some embodiments, tumor antigens include, but are not limited to, ri15,

Not/Me!-40, H-Naz, E2A-RVI, NA-VET, ISN-ISK, MU-KAK, Epstein-Barr virus antigens, EVMA, human papilloma virus (HPV) antigens, including Eb and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigens, TOR-180, rivb5etv2, ri8begtV-3, c-tei, tp-2ZNI, TAa-72-4, CA 19-9, CA 72-4, SAM 17.1, MyMa, K-gaz, rib6, TASE, ROSA, C17, 43-9E, 5T4, 791

Tar72, beta-nHSO, BSA225, VTAA, CA 125, CA 15-3 (CA 27.29.VSAA), CA 195, CA 242, CA-50, SAMAZ,

SOobaZhRI, SO-029, RSE-5, Ca73Z3 (ERSAM), NTor-175, M344, MA-50, Ma7-Ad, IOM18, MV/7/OK, MU-SO-1, VSABI, 5OSSASI16, TA-90 (Mas-2 binding protein/ cyclophilin C-linked protein), TAAI 6, TAC72,

TI R, TR, and the like.

Polynucleotide-containing antigens used in combination with immunogenic compositions described by the authors include polynucleotides that encode polypeptide cancer antigens, for example, those listed above. In some embodiments, polynucleotide-containing antigens include, but are not limited to, DNA or RNA vector constructs, such as plasmid vectors (eg, rom) that are capable of expressing polypeptide cancer antigens ip mimo.

In some embodiments, tumor antigens are derived from mutated or altered cellular components. After the change, the cellular components no longer perform their regulatory functions, and therefore the molecules can have uncontrolled growth. Typical examples of altered cellular components include, but are not limited to, gas, po53, Cr, an altered protein encoded by the Wilms tumor gene, ubiquitin, mucin, a protein encoded by the OSS, ARS, and MCC genes, and receptors or receptor-like structures. , such as neutrons, the thyroid hormone receptor, the platelet-derived growth factor receptor (PGFR), the insulin receptor, the epidermal growth factor receptor (EGR), and the colony-stimulating factor (CSF) receptor.

In addition, bacterial and viral antigens are used in combination with immunogenic compositions proposed by the authors for the treatment of cancer. In some embodiments, carrier proteins such as

CAM 97, tetanus toxoid, or Zaitopeiia iurpitigist antigen, are used in combination/conjugation with the compounds presented by the authors for the treatment of cancer. Anticancer antigen combination therapies show increased efficacy and bioavailability compared to existing treatments.

In some embodiments, immunogenic compositions containing at least one compound of formula (I) include capsular saccharides of at least two of serogroups A, C, M/135 and M from Meizzegia tepipoidev5.

In other embodiments, such vaccines additionally contain an antigen from one or more of the following: (a) serogroup B of M. tepipoiiades; (b) B-type naetorpice, and/or (c) Zigeriosossi5 rpeshtopiae.

In some embodiments, immunogenic compositions containing at least one compound of formula (I) include serogroup C, M/135 and M from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include serogroups A, C, M/135 and M from

M. tepipoiide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include serogroups B, C, M/135 and M from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include serogroups A, B, and C,

M/L135 and U from M. tepipoiidev5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include H. ipPipeplae type B and serogroups C, M/135 and M from M. tepipoide5. In some embodiments, the immunogenic compositions containing at least one compound of formula (I) include H. ipesep7ae type B and serogroups A, C, M/135 and U from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include

N. ipyneplae type B and serogroups B, C, M/135 and MU from M. tepipouyide5. In some embodiments, the immunogenic compositions containing at least one compound of formula (I) include H. ipichep7ae type B and serogroups A, B, C, M/135 and U from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include 5. rpeshtopiae and serogroups C, M/135 and U from M. tepipouiides5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include 5. rpeshtopiae and serogroups A, C, M/135 and B from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (1) include 5. rpeshtopiae and serogroups B, C, M/L35 and M from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include 5. rpeshtopiae and serogroups A, B, C, MU135 and U from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include H. ipbytseplae type B, 5. rpeshtopiae and serogroups C, M/135 and M from M. tepipuyide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include H. ipbytseplae type B, 5. rpeshtopiae and serogroups A, C, MM135 and M from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include H. ipbytseplae type B, 5. rpeshtopiae and serogroups B, C, UM135 and M from M. tepipoide5. In some embodiments, immunogenic compositions containing at least one compound of formula (I) include H. ipitseplae type B, 5. rpeshtopiae and serogroups A, B, C, M/135 and M from M. tepipoidev.

Kits

In addition, the authors proposed pharmaceutical packages or kits, which include one or more containers containing compounds of formula (I) - (XMI), useful for the treatment or prevention of a disease or disorder associated with toll-like receptors. In other embodiments, such pharmaceutical packages or kits include one or more containers containing compounds of formula (Y)-(XMI) useful for the treatment or prevention of a disease or disorder associated with toll-like receptors, and one or several containers containing an additional therapeutic agent, including but not limited to those listed above. In some embodiments, such pharmaceutical packages or kits do not necessarily include instructions for the introduction of the compound of formula (I) - (XMI) described by the authors. In some embodiments of such kits, the compounds of formula (I) - (XMI) are provided in the form of a vaccine composition described by the authors, and, if necessary, the kit includes a syringe for injecting the vaccine composition into the patient.

Methods of treatment, prevention and administration of vaccines

The immunogenic compositions described by the authors can be used in combination with vaccines to improve the immunogenicity of the vaccine, or if the immunogenic composition includes one or more antigens, the immunogenic composition can be used as a vaccine. Therefore, in some embodiments, the immunogenic compositions disclosed by the authors can be used in a method for increasing or enhancing the immune response in mammals, which includes the step of administering an effective amount of the immunogenic composition described by the authors. The immune response is preferably protective and preferably includes antibodies and/or cellular immunity. The method can provoke a booster response.

In some embodiments, the immunogenic compositions disclosed by the authors can be used as a medicine, for example, for use in increasing or enhancing the immune response in mammals.

In some embodiments, the immunogenic compositions disclosed by the authors can be used in the production of a medicinal product to enhance the immune response in mammals.

The invention also provides a delivery device pre-filled with the immunogenic composition described by the authors.

By enhancing the immune response in mammals using these uses and methods, infection in mammals caused by pathogens containing an antigen included in an immunogenic composition or administered in combination with an immunogenic composition can be reduced or even prevented. Mammals are preferably human, but could be, for example, cows, pigs, chickens, cats or dogs, as the pathogens covered by the authors can be problematic in a wide range of species. If the vaccine is intended for prophylactic use, the individual is preferably a child (eg, an infant or child) or an adolescent; if the vaccine is intended for therapeutic use, the individual is preferably an adolescent or adult. A vaccine intended for children can also be administered to adults, for example, to assess safety, dosage, immunogenicity, etc.

One of the ways to check the effectiveness of therapeutic treatment includes monitoring the infectious agent after the introduction of the immunogenic compositions described by the authors. One way to test the effectiveness of preventive treatment involves monitoring the immune response, systemically (such as monitoring the level of production of Ids1 and Ids2a) and/or mucosal (such as monitoring the level of production of IdA), against antigens incorporated into or administered in combination with immunogenic compositions described by the authors, after the introduction of the immunogenic composition (and the antigen, if administered separately). Generally, antigen-specific serum antibody responses are determined after immunization but with challenge, while antigen-specific mucosal antibody responses are determined after immunization and after challenge.

Another method of evaluating the immunogenicity of the immunogenic compositions described by the authors, where the antigen is a protein, consists in the recombinant expression of the protein for screening the serum or mucous secretions of patients by means of immunoblotting and/or microarrays. A positive reaction between the protein and the patient's sample indicates that the patient has an established immune response to the protein in question. This method can also be used to identify immunodominant antigens and/or epitopes in protein antigens.

The effectiveness of the immunogenic compositions can also be determined in situ by challenging appropriate animal models with the pathogen in question.

The immunogenic compositions described by the authors are usually administered directly to the patient. Direct delivery can be achieved by parenteral administration (e.g., subcutaneously, intraperitoneally, intravenously, intramuscularly, or into the interstitial tissue space), or mucosal, e.g., by rectal, oral (e.g., tablets, spray), vaginal, topical, transdermal or transdermal, intranasal, ocular, ear, pulmonary, or other mucosal administration.

Immunogenic compositions can be used to induce systemic and/or mucosal immunity, preferably to induce enhancement of systemic and/or mucosal immunity.

Preferably, enhancement of systemic and/or mucosal immunity is reflected in enhanced TNI1 and/or TN2 immune response. Preferably, enhancement of immune response includes increased production of Ids1 and/or Idsga and/or IdDA.

Dosing can be a single-dose or multiple-dose regimen. Multiple doses can be used in the main vaccination schedule and/or in the booster vaccination schedule. In a multi-dose regimen, different doses can be administered by the same or different routes, for example, parenteral main dose and mucosal booster, mucosal main dose and parenteral booster, etc. Multiple doses are typically administered at least 1 week apart (eg, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 8 weeks, 10 weeks, 12 weeks, about 16 weeks, etc.). d.).

The immunogenic compositions described by the authors, including one or more antigens or used in combination with one or more antigens, can be used to treat children and adults. Thus, a human patient can be less than 1 year old, 1-5 years old, 5-15 years old, 15-55 years old, or at least 55 years old. The optimal patients for receiving such immunogenic compositions are the elderly (for example, » 50 years, over 60 years, and, preferably, » 65 years), younger age (for example, "5 years), hospitalized patients, health care workers, military and military personnel, pregnant women, chronically ill, or immunocompromised patients. Immunogenic compositions are not suitable only for these groups, but can be used in the population as a whole.

The immunogenic compositions described by the authors, comprising one or more antigens or used in combination with one or more antigens, may be administered to patients at substantially the same time (eg, during a medical consultation or physician visit or vaccination center) as other vaccines, for example, at almost the same time as the measles vaccine, the mumps vaccine, the rubella vaccine, the MME vaccine, the chicken pox vaccine, the

MMEU, diphtheria vaccine, tetanus, pertussis vaccine, AKDP vaccine, N. ipishep/lae type B conjugate vaccine, inactivated poliomyelitis vaccine, hepatitis B virus vaccine, meningococcal conjugate vaccine (eg, tetravalent AS M /135 U), vaccine against respiratory syncytial virus, etc.

Examples

The following examples are presented to illustrate, and not to limit, the compounds of Formula (I) provided herein and the preparation of such compounds.

Preparation of benzoshP,7|Inaphthyridin-5-amine analogs

Example 1

BenzoSHI,7|naphthyridine-5-amine

MN"

M M

-

A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromopicolinonitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol ) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 V of methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 95 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mo95O4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGAZNO system (IZSO) using 0-80 96 ethyl acetate in hexane to give a white solid. "H NMR (acetone a-6): b 9.04 (a, 1H), 8.91 (a, 1H), 8.45 (a, tn), 7.86 (aa, 1H), 7.53 -7.62 (t, 2H), 7.35 (i, 1H), 6.65 (g, 2H). And AM5 (MANI - 196.1

Example 2

Pyrazine|2,3-s|quinoline-5-amine

MN" more

She

M

A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloropyrazine-2-carbonitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenylphosphine)palladium ( 5 mole beans) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous M95O", and concentrated in vacuo. The crude product is purified by flash chromatography on a SOMBIRGA5NO system (IZSO) using 0-50 90 ethyl acetate in hexane to give a solid. "H NMR (acetone a-6): b 9.14 (5, 1H), 8.95 (5, 1H), 8.77 (a, tn), 7.63-7.66 (t, 2H) , 7.38 (i, 1H), 6.77 (BI, 2H). And VM5 (MANI - 197.1

Example With 9-chlorobenzo| DI, 7-Naphthyridin-5-amine

MN"

MU M d

SI

Stage 1: tert-butyl 2-bromo-4-chlorophenylcarbamate

To a solution of 2-bromo-4-chloroaniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a M" atmosphere, 1M ManNmoz (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMBIRSABNOE system (I5CO) using 0-590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Stage 2: tert-butyl 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl-carbamate)

Tert-butyl. 2-bromo-4-chlorophenylcarbamate (from step 1) (1.0 equiv.), 4,4,44,5,5,5,5'-octamethyl-2,2/- bi(1,3,2- dioxaborolane) (1.5 eq.), dichloro|1,1"-bisidiphenylphosphino)-ferrocene|palladium (I) (5 95), and sodium acetate (4.5 eq.) are mixed in dioxane (0.2 M) in M" atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in a vacuum. The crude mixture is purified using flash chromatography on the SOMVIRGAZNO system (IZSO), using 0-95 ethyl acetate in hexane to give tert-butyl 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl-carbamate).

Stage 3: 9-ChlorobenzoShP, 7|Inaphthyridin-5-amine

A solution of tert-butyl 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl carbamate (from step 2) (1.0 eq.) and 3-bromopicolino -nitrile (1.0 equiv) in toluene (0.44 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2 M aqueous potassium carbonate (2.0 equiv). The reaction mixture was heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases were washed with brine, dried over anhydrous Mo95O", and concentrated in a vacuum.

The crude product is purified by flash chromatography on a SOMBGABZNFFO system (IZSO) using 0-50 95 ethyl acetate in hexane and then purified again using 0-5 96 methanol in dichloromethane to give a solid. "H NMR (acetone a-6): b 9.08 (y, 1), 8.96 (9, 1H), 8.45 (5, 1H), 7.86-7.89 (aa, 1H) , 7.60 (a, 1), 7.54 (a, 1Hn), 6.78 (ri, 2H). I AM5 |M.ANI - 230.1

Example 4 8-chlorobenzo DI, 7-naphthyridin-5-amine

MN" again ak: -

SI

Stage 1: tert-butyl 2-bromo-5-chlorophenylcarbamate

To a solution of 2-bromo-5-chloroaniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a M" atmosphere, 1M ManNmoz (2.5 equiv.) was added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

to the SOMVIBSABNOE system (I5CO), using 0-5590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Stage 2: tert-butyl 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl-carbamate)

Tert-butyl 2-bromo-5-chlorophenylcarbamate (from step 1) (1.0 equiv), 4,4,44,5,5,5,5'-octamethyl-2,2/- bi(1,3 ,2-dioxaborolane) (1.5 eq.), dichloro|1,1"-bisidiphenylphosphino)-ferrocene|palladium (I) (5 95), and sodium acetate (4.5 eq.) are mixed in dioxane (0, 2 M) in M" atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in a vacuum. The crude mixture is purified using flash chromatography on the SOMVIRGAZNO) system ( ИЗСО), using 0-95 ethyl acetate in hexane, which gives tert-butyl 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl-carbamate).

Stage 3: 8-chlorobenzo DP, 7|Inaphthyridin-5-amine

A solution of tert-butyl 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino -nitrile (1.0 equiv) in toluene (0.44 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2 M aqueous potassium carbonate (2.0 equiv). The reaction mixture was heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases were washed with brine, dried over anhydrous M95O54, and concentrate in a vacuum.

The crude product is purified by flash chromatography on a SOMVIBGABZNFO system (IZSO) using 0-5 96 methanol in dichloromethane to give a semi-pure solid, which is then stirred in hot 10 95 ethyl acetate in hexane, filtered, and dried to give obtaining a pure solid substance. "H NMR (acetone a-6): b 9.03 (y, 1H), 8.93 (a, 1H), 8.46 (9, 1H), 7.85-7.88 (ad, 1H) , 7.57 (5, 1H), 7.32 (a, 1H), 6.94 (ri, 2H). And AM5 (MANI - 230.1

Example 5 8-methylbenzo| DI, 7|naphthyridine-5-amine

MN

M M, d

Stage 1: tert-butyl 2-bromo-5-methylphenylcarbamate

To a solution of 2-bromo-5-methylaniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a Mo atmosphere, 1M ManNmoz (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNOE system (I5CO), using 0-590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Stage 2: tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate)

tert-butyl 2-bromo-5-methylphenylcarbamate (from step 1) (1.0 equiv.), 4,4,44,5,5,5,5'-octamethyl-2,2/- bi(1,3 ,2-dioxaborolane) (1.5 eq.), dichloro|1,1"-bisidiphenylphosphino)-ferrocene|palladium (I) (5 95), and sodium acetate (4.5 eq.) are mixed in dioxane (0, 2 M) in M" atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in a vacuum. The crude material is purified using flash chromatography on the SOMVIRGAZNO) system ( IZSO), using 0-895 ether in hexane, which gives tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/phenylcarbamate).

Stage 3: 8-methylbenzo DP, 7-Naphthyridin-5-amine

A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl-carbamate (from step 2) (1.0 eq.) and 3-bromopicolino -nitrile (1.0 equiv) in toluene (0.44 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2 M aqueous potassium carbonate (2.0 equiv). The reaction mixture was heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases were washed with brine, dried over anhydrous M95O54, and concentrate in a vacuum.

The crude product is purified by flash chromatography on a SOMVIBGABZNFO system (IZSO) using 0-40% ethyl acetate in toluene to give a pure solid.

NMR (acetone a-6): b 8.98 (y, 1H), 8.687 (9, 1H), 8.32 (a, 1H), 7.79-7.82 (ad, 1H), 7, 42 (5, 1H), 7.18 (y, 1H), 6.6 (rt, 2H), 2.45 (5, ЗН). And AM5 | MA-NI - 210.1

Example 6 9-methylbenzo| DI, 7|naphthyridine-5-amine

MN" aka: -

Stage 1: tert-butyl 2-bromo-4-methylphenylcarbamate

To a solution of 2-bromo-4-methylaniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a M" atmosphere, 1M ManNmoz (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNOE system (I5CO), using 0-590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Stage 2: tert-butyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate)

Tert-butyl 2-bromo-4-methylphenylcarbamate (from step 1) (1.0 equiv.), 4,4,4,4,5,5,5,5'-octamethyl-2,2/- bi(1 . 0.2 M) in M" atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in vacuo. The crude material is purified using flash chromatography on SOMVIRGAZNO) system (IZSO) using 0-895 ether in hexane, which leads to tert-butyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/phenylcarbamate) .

Stage 3: 9-methylbenzo DP, 7-Naphthyridin-5-amine

A solution of tert-butyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino -nitrile (1.0 equiv) in toluene (0.44 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2 M aqueous potassium carbonate (2.0 equiv). The reaction mixture was heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases were washed with brine, dried over anhydrous Mu95O54, and concentrate in a vacuum.

The crude product is purified using flash chromatography on the SOMBIBGABZNFO system (IZSO),

using 0-5 96 methanol in dichloromethane to give a semi-pure solid, which was then stirred in hot ethyl acetate, filtered, and dried to give a pure solid. "H NMR (acetone a-6): b 9.02 (y, 1H), 8.89 (y, 1H), 8.25 (5, 1H), 7.80-7.84 (aa, 1) , 7.52 (a, 1), 7.40 (a, 1H), 6.5 (Bg, 2H), 2.48 (z, ZN). And AM5 MANI - 210.2

Example 7 10-methylbenzo DI, 7-inaphthyridin-5-amine

to me

M | MD

Stage 1: tert-butyl 2-bromo-3-methylphenylcarbamate

To a solution of 2-bromo-3-methylaniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a Me2 atmosphere, 1M ManNmoz (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMBIRSABNOE system (I5CO) using 0-590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Stage 2: tert-butyl 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate)

Tert-butyl 2-bromo-3-methylphenylcarbamate (from step 1) (1.0 equiv), 4,4,4,4,5,5,5,5'-octamethyl-2,2/- bi(1 . 0.2 M) in M" atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in vacuo. The crude material is purified using flash chromatography on SOMVIRGAZNO) system (IZSO), using 0-95 ether in hexane, to obtain tert-butyl 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate.

Stage 3: 10-methylbenzo|CP1, 7UInaphthyridin-5-amine

A solution of tert-butyl 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino -nitrile (1.0 equiv) in toluene (0.44 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2 M aqueous potassium carbonate (2.0 equiv). The reaction mixture was heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases were washed with brine, dried over anhydrous Mo95O", and concentrated in a vacuum.

The crude product is purified by flash chromatography on a SOMVIBGABZNFO system (IZSO) using 0-40 95 ethyl acetate in toluene to give a semi-pure solid, which is then stirred in hot 10 95 ethyl acetate in hexane, filtered, and dried to give obtaining a pure solid substance. "H NMR (acetone a-6): b 9.22 (y, 1n), 8.90 (a, 1n), 7.82-7.85 (ai, 1), 7.54 (y, 1H) .

Example 8

Ethyl 5-aminobenzo H(1,7|naphthyridine-9-carboxylate

MN"

M M

- that's it"

Stage 1: Ethyl 3-bromo-4-(tert-butoxycarbonylamino)benzoate

To a solution of 4-amino-3-bromobenzoate (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a Mo atmosphere, 1M Manmo5 (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950O5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNOE system (I5CO), using 0-590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Stage (2: Ethyl 4-(tert-butoxycarbonylamino)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Ethyl 3-bromo-4-(tert-butoxycarbonylamino)benzoate (from step 1) (1.0 eq), 44,44,5,5,5,5- octamethyl-2,2/-6i(1,3, 2-dioxaborolane) (1.5 eq.), dichloro|1,1-bisidiphenylphosphino)ferrocene|palladium(II) (590), and sodium acetate (4.5 eq.) are mixed in dioxane (0.2 M) in Me atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The obtained suspension is cooled to room temperature, diluted with ether, filtered through celite, and the filtrate is concentrated in a vacuum.

The crude material is purified by flash chromatography on the SOMVIRG ABNO system (IZSO), using 0-10 95 ether in hexane, which leads to the production of oethyl 4-(tert-butoxycarbonylamino)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-benzoate.

Stage 3: Ethyl 5-aminobenzo DP, 7|Inaphthyridine-9-carboxylate

A solution of ethyl 4-(tert-butoxycarbonylamino)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (from step 2) (1.0 equiv.) and C -bromopicolinonitrile (1.0 equiv.) in a mixture of toluene/ethanol (10:1, 0.23

M) is mixed with tetrakis(triphenyl-phosphine)palladium (5 mol) and anhydrous potassium carbonate (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 95 methanol in dichloromethane. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMBIRGABNO system (I5CO) using 0-40 90 ethyl acetate in toluene to give a semi-pure solid, which is then stirred in hot 10 95 ethyl acetate in hexane, filtered, and dried to give a pure solid. "H NMR (acetone a-6): 6 9.11 (a, 1H), 9.05 (5, 1H), 8.95 (a, 1H), 8.14 (a, 1H), 7.89 -7.92 (aa, 1H), 7.63 (9, 1H), 4.38 (9, 2H), 1.40 y, ЗН. G eM5 (MANI - 268.2.

Example 9

B-aminobenzo CY, 7-Naphthyridine-9-carboxylic acid

MN"

MU Mo d o on

Ethyl 5-aminobenzo DY, 7|Inaphthyridine-9-carboxylate (Example 8) (1.0 eq.) is mixed with 1 M Mammon (2.0 eq.) in ethanol (0.12 M). The reaction mixture is heated to 802C and stirred for 36 hours.

The solvent is removed in vacuo. The residue is suspended in water, and the pH is brought to neutral using 5 95 aqueous solution of citric acid. The suspension is centrifuged (2500 rpm, 5 min.), and the supernatant liquid is removed. The resulting solid is resuspended in water by shaking, centrifuged (2500 rpm, 5 min.), and the supernatant is removed. The steps of resuspension, centrifugation, and supernatant removal are repeated with hot methanol, hot ethyl acetate, and ether, resulting in a pure solid.

NMR (DMSO): b 12.86 (5, 1H), 9.15 (a, 1H), 9.00 (5, 1H), 8.97 (a, 1H), 8.07 (a, 1Hn ), 7.88-7.91 (aa, tn), 7.56-7.59 (t, ZN). GAM5 |M--NO - 240.1

Example 10 8-methoxybenzo|PCI1,7|Inaphthyridin-5-amine

MN" dog: d - c)

Stage 1: 2-bromo-5-methoxyaniline

A solution of 1-bromo-4-methoxy-2-nitrobenzene (1.0 equiv), powdered iron (3.0 equiv), and concentrated HCl (1.04 equiv) were mixed together in ethanol (0.64 M) and heated to irrigation.

The reaction mixture was stirred for 24 hours, and the solvent was evaporated. The resulting residue is diluted with ethyl acetate and a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted three times with ethyl acetate, and the combined organic phases were washed with water, brine, dried over anhydrous Md5O5, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBGABNO system (IZSO) using 0-15 95 ethyl acetate in hexane, which gives the product as an oil.

Stage 2: tert-butyl 2-bromo-5-methoxyphenylcarbamate

To a solution of 2-bromo-5-methoxyaniline (1.0 equiv.) (from stage 1) in tetrahydrofuran (0.2 M) at 02C in a Me atmosphere, 1M Manmo5 (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added.

The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M NOSI aqueous solution. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Mo95O4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGABNO system (IZSO) using 0-5 905 ethyl acetate in hexane to give the product as a light yellow oil.

Stage 3: tert-butyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-ylphenylcarbamate)

tert-butyl 2-bromo-5-methoxyphenylcarbamate (from step 2) (1.0 equiv), 4,4,4,4,5,5,5,5'-octamethyl-2,2/- bi(1 ,3,2-dioxaborolane) (1.5 eq.), dichloro|/1,1"-bisidiphenylphosphino)-ferrocene|palladium (I) (5 95), and sodium acetate (4.5 eq.) are mixed in dioxane (0.2 M) in M" atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in vacuo. The crude material is purified by flash chromatography on SOMBIRGASNO ) system (IZSO) using 0-1595 ether in hexane, which leads to tert-butyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbamate.

Stage 4: 8-methoxybenzo DI, 7|naphthyridine-5-amine

A solution of tert-butyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate (from step 3) (1.0 eq.) and 3-bromopicolino -nitrile (1.0 eq.) in toluene/ethanol (10:1, 0.23 M) was mixed with tetrakis(triphenylphosphine)palladium (5 molbo) and anhydrous potassium carbonate (2.0 eq.). the mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 3 296 methanol in dichloromethane.

The combined organic phases are washed with brine, dried over anhydrous Mo5O", and concentrated in vacuo. The crude product is purified by flash chromatography on

SOMBIRGABNO system (IZSO) using 0-5 9% methanol in dichloromethane to give a semi-pure solid, which is then recrystallized from ethyl acetate, filtered, and dried to give a pure solid. "H NMR (acetone a-6): b 8.91 (y, 1H), 8.82 (a, 1n), 8.33 (a, 1H), 7.76-7.79 (aa, 1H) .

Example 11 7-fluorobenzo|(DI1, Yanaftyridin-5-amine

MN"

MU | Me

IS -

Stage 1: tert-butyl 2-fluorophenylcarbamate

To a solution of 2-fluoroaniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a Mo atmosphere, 1M Manmoz (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of NaCl. The aqueous suspension is extracted twice with ethyl acetate.

The combined organic phases are washed with brine, dried over anhydrous Moa50O", and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVIRGSABNOE system (I5CO), using 0-590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Stage 2: 2-(tert-butoxycarbonylamino)-3-fluorophenylboronic acid

To a solution of tert-butyl 2-fluorophenylcarbamate (from stage 1) (1.0 equiv.) in tetrahydrofuran (0.25 M) at -782C in a Mo atmosphere, 1.7 M tert-butyllithium (2.4 equiv.) is added dropwise. ). The reaction mixture is heated to -402C slowly over 2 hours, and undiluted trimethyl borate (3.8 eq.) is added. The reaction mixture is heated to room temperature for 30 minutes. Aqueous solution 1M

Mahon was slowly added to this reaction mixture and stirred for 15 minutes. This mixture is poured into ethyl acetate and acidified with ZM NOSI to dissolve the solids. The aqueous layer was extracted twice with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous Mu950O.5, and concentrated in vacuo. The resulting solid is stirred in a 1:1 mixture of ether/hexane, filtered, and dried. The solid substance is transferred to the next stage without additional purification.

Stage 3: 7-fluorobenzo|Ш/1,7|naphthyridin-5-amine

A solution of 2-(tert-butoxycarbonylamino)-3-fluorophenylboronic acid (from step 2) (1.0 eq.) and 3-bromopicolinonitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakiss ( triphenyl-phosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (2.0 eq.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 95 methanol in dichloromethane. The combined organic phases are washed with saline solution, dried over anhydrous Md5O", and concentrated in vacuo. After the usual work-up, the crude product is suspended in hot toluene, centrifuged (2500 rpm, 5 min.), and the supernatant is removed. The suspension, centrifugation, and supernatant removal steps are repeated with hot ethyl acetate, ether, and hexane to give a pure solid. "H NMR (acetone a-6): b 9.04 (a, 1H), 8.96 (a, 1H), 8.27 (9, 1H), 7.86-7.90 (ad, 1H) , 7.28-7.34 (t, 2H), 6.9 (ri, 2H). GG AM5 | MANI - 214.1

Example 12 8-(methylsulfonyl)benzo CH, 7|Inaphthyridin-5-amine

Mn" aka: d 7 vo

Stage 1: 2-bromo-5-(methylsulfonyl)aniline

A solution of 1-bromo-4-(methylsulfonyl)-2-nitrobenzene (1.0 eq.), powdered iron (3.0 eq.), and concentrated HCl (1.04 eq.) were mixed together in ethanol (0.64 M) and heated to irrigation.

The reaction mixture was stirred for 24 hours, and the solvent was evaporated. The resulting residue is diluted with ethyl acetate and a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted three times with ethyl acetate, and the combined organic phases were washed with water, brine, dried over anhydrous Md5O5, and concentrated in vacuo. The crude material was purified by trituration in a 1:1 mixture of hexane/ether to give a light yellow solid.

Stage 2: tert-butyl 2-bromo-5-(methylsulfonyl)/phenylcarbamate

To a solution of 2-bromo-5-(methylsulfonyl)aniline (from stage 1) (1.0 equiv.) in tetrahydrofuran (0.2 M) under 02Сb in M» atmosphere, 1M Manmose (2.5 equiv.) is added dropwise. . The reaction mixture is stirred for 15 minutes at 09C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous M950O»4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMVIRGA5NO system (IZSO) using 0-5 95 ethyl acetate in hexane to give tert-butyl 2-bromo-5-(methylsulfonyl)phenylcarbamate.

Stage C: tert-butyl 5-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate

Tert-butyl. 2-bromo-5-(methylsulfonyl)/phenylcarbamate (from stage 2) (1.0 equiv.), 4,4,44,5,5,5,5'-octamethyl-2,2/-6i(1, 3,2-dioxaborolane) (1.5 eq.), dichloro|1,1-bisidiphenylphosphino)ferrocenipalladium(II) (590), and sodium acetate (4.5 eq.) are mixed in dioxane (0.2 M) in Me atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The obtained suspension is cooled to room temperature, diluted with ether, filtered through celite, and the filtrate is concentrated in a vacuum.

The crude material is purified by flash chromatography on a SOMVIRGAZNF system (IZSO) using 0-50 95 ethyl acetate in hexane, which gives a solid, which is then triturated in a mixture of 10 95 ether/hexane, which gives tert-butyl 5- (methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)uphenylcarbamate as a white solid.

Stage 4: 8-(methylsulfonyl)benzo CY, 7|naphthyridin-5-amine

A solution of tert-butyl 5-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 3) (1.0 equiv.) and C -bromopicolinonitrile (1.0 eq.) in toluene (0.24 M) is mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (4.0 eq.).

The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases are separated and the aqueous layer is extracted twice with 295 methanol in dichloromethane.

The combined organic phases are washed with saline, dried over anhydrous Mo5O", and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMBIRGABNO system (IZSO) using 0-5 9o methanol in dichloromethane, which gives a solid which is then triturated in a 1:1 mixture of hexane/ethyl acetate, which gives 8-(methylsulfonyl)-benzo|C/1.7 Inaphthyridine-5-amine. "H NMR (acetone a-6): b 9.16 (y, 1H), 9.03 (y, 1), 8.71 (a, 1H), 8.11 (c, 1H), 7.93 -7.96 (aa, 1), 7.81 (a, 1), 7.0 (bg, 2H), 3.19 (c, ZN). I VM5

IMANI - 2741

Example 13 8-(trifluoromethyl)benzo C(1,7|Inaphthyridin-5-amine

Me aa: -

Es

Stage 1: tert-butyl 2-bromo-5-(trifluoromethyl)phenylcarbamate

To a solution of 2-bromo-5-(trifluoromethyl)aniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 09C in a Me atmosphere, 1M Manmo5 (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added.

The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M NOSI aqueous solution. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Mo95O4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGABNO system (IZSO) using 0-5 905 ethyl acetate in hexane to give the product as a light yellow oil.

Stage 2: tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenylcarbamate

Tert-butyl. 2-bromo-5-(trifluoromethyl)phenylcarbamate (from stage 1) (1.0 eq), 4,4,44,5,5,5,5- octamethyl-2,2/-6i(1,3,2 -dioxaborolane) (1.5 equiv.), dichloro|1,1-bisidiphenylphosphino)ferrocenipalladium (II) (590), and sodium acetate (4.5 equiv.) are mixed in dioxane (0.2 M) under a Me atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The obtained suspension is cooled to room temperature, diluted with ether, filtered through celite, and the filtrate is concentrated in a vacuum.

The raw material is purified by means of flash chromatography on the SOMVIRGAZNF system (IZSO), using 0-10 95 ether in hexane, which leads to the receipt of a contaminated product, which is transferred to the next stage without additional purification.

Stage 3: 8-(trifluoromethyl)benzo OR, 7|naphthyridin-5-amine

Tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenylcarbamate solution (from step 2) (1.0 equiv.) and 3-bromopicolinonitrile (1.0 eq.) in toluene (0.24 M) were mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2M aqueous potassium carbonate (4.0 eq.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 295% methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 95 methanol in dichloromethane. The combined organic phases are washed with saline solution, dried over anhydrous

M95O", and concentrate in a vacuum. The crude product is purified by flash chromatography on

SOMBIRGABNO system (I5CO) using 0-40 90 ethyl acetate in toluene, which gives a solid, which is then triturated in 10 95 ethyl acetate in hexane, which gives 8-(trifluoromethyl)-benzoI, 7|naphthyridine-5- amine "H NMR (acetone a-6): b 9.13 (y, 1H), 9.00 (a, 1H), 8.67 (9, 1H), 7.91-7.94 (aa, 1H) , 7.86 (c, 1H), 7.58 (a, 1H), 6.9 (Bi, 2H). GAM5 |MA-NI - 264.1

Example 14 8-fluorobenzo|(DI1,7Yinaphthyridin-5-amine

MN" aka: dy

IS

Stage 1: tert-butyl 2-bromo-5-fluorophenylcarbamate

To a solution of 2-bromo-5-fluoroaniline (1.0 equiv.) in tetrahydrofuran (0.2 M) at 02С in a Me2 atmosphere, 1M ManNmoz (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 02C, and a solution of di-tert-butyl dicarbonate in tetrahydrofuran is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with a 0.1 M aqueous solution of HCl. The aqueous suspension is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

to the SOMVIBSABNOE system (I5CO), using 0-5590 ethyl acetate in hexane, which gives the product as a light yellow oil.

Step 2: tert-butyl 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)/uphenylcarbamate

Tert-butyl. 2-bromo-5-fluorophenylcarbamate (from step 1) (1.0 equiv.), 4,4,44,5,5,5,5'-octamethyl-2,27-bi(1,3,2-dioxaborolane ) (1.5 equiv.), dichloro|1,1"-bisidiphenylphosphino)-ferrocene|palladium (I) (5 95), and sodium acetate (4.5 equiv.) are mixed in dioxane (0.2 M) in M" atmosphere. The reaction mixture is heated to 1002C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in vacuo. The crude material is purified by flash chromatography on a SOMVIRGAZNO) system (IZSO) using 0- to ether in hexane to give the product as a yellow solid.

Stage 3: 8-fluorobenzo|CP1,7|naphthyridine-5-amine

A solution of tert-butyl 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl carbamate (from step 2) (1.0 eq.) and 3-bromopicolino -nitrile (1.0 equiv) in toluene (0.24 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2 M aqueous potassium carbonate (4.0 equiv). The reaction mixture was heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases were washed with brine, dried over anhydrous Mu95O54, and concentrate in a vacuum.

The crude product is purified by flash chromatography on a SOMVIBGABNO system (IZSO) using 0-40 96 ethyl acetate in toluene to give a solid, which is then triturated in 1095 ethyl acetate in hexane to give 8-fluorobenzo|PC1.7 Inaphthyridine-5-amine. "H NMR (acetone a-6): b 9.00 (a, 1H), 8.90 (a, 1H), 8.46-8.50 (aa, 1H), 7.83-7.87 ( aa, 1), 7.26 (9, 1), 7.15 (, 1), 6.9 (g, 2H). AND AM5 IM-NI - 2141

Example 15

B-aminobenzo CY, 7Inaphthyridin-Z(4H)-one

MN" N

M M. ao s d

Stage 1: 3-bromo-2-cyanopyridine 1-oxide

To a solution of 33-bromopicolinonitrile (1.0 equiv.) in chloroform (0.3 M) was added 7795 meta-chloroperbenzoic acid (pSRBA) (1.8 equiv.) and heated at 609C for 2 days. After cooling to room temperature, Ca(OnH)" (2.5 eq.) is added, and the resulting precipitate is stirred for 30 minutes. The precipitate is filtered and washed with 595% methanol in dichloromethane. The filtrate is washed with a saturated aqueous solution of ManHsCO3. The aqueous layer is extracted several times with C 95 methanol in dichloromethane. The combined organic phases were dried over anhydrous Md5Ox and concentrated in vacuo. The crude product is stirred in hot hexane/ethyl acetate (1:1), filtered, and dried to give the desired product as a white solid.

Step 2: 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile

A solution of 3-bromo-2-cyanopyridine 1-oxide (from stage 1) in acetic anhydride (0.5 M) is heated at 1502C for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue is cleaned using the SOMVIBSGABNYA system (IZSO),

using 0-90 95 ethyl acetate in hexane to give O-acetate, which is hydrolyzed in 2M MOH/methanol (1:1, 0.2M) at room temperature for 2 hours. The resulting mixture is diluted with water and acidified with 5 95 citric acid. The pale yellow precipitate was filtered and washed with a 9:1 mixture of hexane/ethyl acetate and ether to give 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile.

Step 3: 3-bromo-6-(tert-butyldimethylsilyloxy)picolinonitrile

A solution of 3-bromo-6b-oxo-1,6-dihydropyridine-2-carbonitrile (from step 2) (1.0 eq.), tert-butyldimethylsilyl chloride (TBZSI) (1.8 eq.), and imidazole (2, 5 eq.) in DMF (0.2 M) was heated to 6020 and stirred overnight. The reaction mixture is diluted with water and extracted with ether. The combined organic phases were dried over anhydrous M95O4 and concentrated in vacuo. The residue is purified using the SOMVIBRSABN system (I5CO) using 0-20 90 ethyl acetate in hexane to give 3-bromo-6-(tert-butyldimethylsilyloxy)picolinonitrile.

Stage 4: 3-(tert-butyldimethylsilyloxy)benzo DY, 7|naphthyridin-5-amine

A solution of 2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq.) and 3-bromo-6-(tert-butyldimethylsilyloxy)picolinonitrile (from step 3) (1.0 eq.) in a mixture of toluene/ethanol (10: 1, 0.2 M) is mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 95 methanol in dichloromethane. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO), using 0-50 90 ethyl acetate in hexane, which leads to a solid.

Stage 5: 5-aminobenzo DY 7Y|naphthyridin-3(4H)-one

To a solution of 3-(tert-butyldimethylsilyloxy)benzo CHY,7|naphthyridine-5-amine (from stage 4) (1.0 equiv.) in tetrahydrofuran (0.05 M) is added tetra-n-butylammonium fluoride (TVABE) ( 1.0 equiv.) and acetic acid (1.0 equiv.). The reaction mixture was stirred for 15 minutes and then concentrated in vacuo. The crude residue is suspended in water and neutralized by adding a saturated aqueous solution of MansSoO» to pH 7. The solid substance is filtered, washed with acetone, and dried, which leads to the preparation of 5-aminobenzo DY, Yainanaphthyridin-3(4H)-one. "H NMR (DMSO a-6): b 8.59 (a, 1H), 8.20 (a, 1Hn), 7.49 (a, 1), 737-741 (aa, 1), 7.23 -7.27 (ad, 1H), 6.88 (Bg, 2H), 6.79 (a, 1n). H eMm5 |M-ANI - 212.1

Example 16

Z-methoxybenzo| DI, 7|naphthyridine-5-amine

Mne ka s | d

Stage 1: 3-bromo-b-methoxypicolinonitrile

A solution of 3-bromo-6b-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15 / Step 2) (1.0 eq.), silver carbonate (1.3 eq.), and iodomethane (1.2 equiv) in toluene (0.2 M) was stirred in the dark at room temperature overnight. The solvent is concentrated in vacuo, and the resulting residue is purified using a SOMBIRSABB system (I5CO) using 0-80 90 ethyl acetate in hexane to give 3-bromo-6b-methoxypicolinonitrile.

Stage 2: Z-methoxybenzo DI, 7|naphthyridine-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq) and 3-bromo-6-methoxypicolinonitrile (from step 1) (1.0 eq) in toluene (0.44 M) is mixed with tetrakis(triphenyl - phosphine)palladium (5 mol) and a 2M aqueous solution of potassium carbonate (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 95 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMVIBGABZNFO system (IZSO) using 0-5095 ethyl acetate in hexane, which gives /-3-methoxybenzo|(1,7Inaphthyridin-5-amine) as a yellow solid. "H NMR ( acetone a-6): b 8.91 (a, 1Hn), 8.34 (9, 1), 7.63 (a, 1), 7.51-7.53 (da, 1H), 7.27 -7.33 (t, 2H), 6.65 (Brg, 2H), 4.11 (5, ZN).

GAM5IMANI - 226.1

Example 17

Z-butoxybenzo|ЦЙ1,7|naphthyridin-5-amine

MN"

M Myt s -

Stage 1: 3-bromo-6-butoxypicolinonitrile

A solution of 3-bromo-6b-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15 / Step 2) (1.0 eq.), potassium carbonate (1.3 eq.), and 1-iodobutane (1 .2 equiv.) in acetone (0.3 M) is stirred at 702C overnight. The solvent is concentrated in vacuo, and the resulting residue is taken up in water and ethyl acetate.

The aqueous layer was extracted with ethyl acetate three times. The combined organic phases are washed with saline, dried over anhydrous Mo95O4, and concentrated in vacuo. The crude product is purified using the SOMBIRI AZNO system (IZSO) using 0-30 9o ethyl acetate in hexane to give a colorless solid.

Stage 2: 3-butoxybenzo CH, 7|Inaphthyridin-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq) and 3-bromo-6-butoxypicolinonitrile (from step 1) (1.0 eq) in toluene (0.44 M) is mixed with tetrakis(triphenyl - phosphine)palladium (5 mol) and a 2M aqueous solution of potassium carbonate (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 95 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMVIBGABZNFFO system (IZSO) using 0-5590 ethyl acetate in methanol to give /-3-butoxybenzo|C1,7|Inaphthyridin-5-amine as a white solid. "H NMR (acetone a-6): b 8.91 (ad, 1), 8.34 (a, 1), 7.61 (y, 1), 7.48-7.52 (ad, 1H) , 7.27-7.33 (t, 2H), 6.51 (rg, 2H), 6.55 (i, 2H), 1.81-1.88 (t, 2H), 1.50-1 .59 (t, 2H), 1.00 (i, ZN). And AM5 (MANI - 268.1

Example 18

Z-(benzyloxy)benzo DP, 7|Inaphthyridin-5-amine that match MO with | -

Stage 1: 6-(benzyloxy)-3-bromopicolinonitrile

A solution of 3-bromo-6b-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15 / Step 2) (1.0 equiv), silver carbonate (1.3 equiv), and benzyl bromide (1.2 equiv.) in toluene (0.16 M) is stirred in the dark at 50C overnight. The solvent is concentrated in vacuo, and the resulting residue is purified using a SOMBIRSABB system (I5CO) using 0-20 90 ethyl acetate in hexane to give 6-(benzyloxy)-3-bromopicolinonitrile.

Stage 2: 3-(benzyloxy)benzo| 1, 7|naphthyridine-5-amine

A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and b6-(benzyloxy)-3-bromopicolinonitrile (from step 1) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis (triphenylphosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mo95O»4, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMVIBGABZNFFO system (IZSO) using 0-5095 ethyl acetate in hexane to give /-3-(benzyloxy)benzo| DI, 7|naphthyridine-5-amine as a yellow solid. "H NMR (acetone a-6): b 8.95 (a, 1H), 8.35 (a, 1H), 7.58-7.63 (t, 2H), 7.49-7.53 ( ai, 1H), 7.30-7.44 (t, 5H), 6.61 (Brg, 2H), 5.64 (5, 2H). GAMm5 MANI - 302.1

Example 19

3-Methylbenzoic acid, 7-Naphthyridin-5-amine

Mn aa: p

Stage 1: 5-bromo-2-methylpyridine 1-oxide

To a solution of 5-bromo-2-methylpyridine (1.0 equiv.) in chloroform (0.38 M) was added 7795 meta-chloroperbenzoic acid (pSRBA) (4.0 equiv.) and heated at 602C for 20 hours. After cooling to room temperature, Ca(OH)" (5.3 eq.) was added, and the resulting precipitate was stirred for 30 minutes. This precipitate is filtered and washed with a 3:1 CHCl/methanol mixture.

The filtrate is concentrated in vacuo to give a solid which is taken up in 95% ethyl acetate in hexane and filtered to give the desired M-oxide. The filtrate is concentrated in vacuo and the residue is purified by a SOMVIRGAS system (IZSO) using 0-100 95 ethyl acetate in hexane to afford more of the desired

M-oxide. The two batches are combined and transferred to the next stage.

Stage 2: 3-bromo-b-methylpicolinonitrile

To a solution of 5-bromo-2-methylpyridine 1-oxide (from stage 1) (1.0 equiv.) in acetonitrile (0.2 M) is added trimethylsilyl cyanide (TM5SM) (4.0 equiv.) and triethylamine (3 .0 equiv.). The reaction mixture is heated at 1002C overnight. After cooling to room temperature, the solvent is concentrated in vacuo, and the residue is purified using a SOMVIRGAZNO system (IZSO) using 0-50 95 ethyl acetate in hexane to give 3-bromo-6-methylpicolinonitrile.

Stage 3: 3-methylbenzo DP, 7-Naphthyridin-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq) and 3-bromo-6-methylpicolinonitrile (from step 2) (1.0 eq) in toluene (0.44 M) is mixed with tetrakis(triphenyl - phosphine)palladium (5 mol) and a 2M aqueous solution of potassium carbonate (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMBIRGAS system (IZSO) using 0-70905 ethyl acetate in hexane to give /-3-methylbenzox/1,7|inaphthyridin-5-amine as a yellow solid. "H NMR (methanol a-4): b 8.85 (a, tn), 8.38 (a, 1H), 7.72 (a, 1H), 7.53-7.61 (t, 2H) , 7.34-7.38 (ad, 1H), 2.76 (5, ZN). And AM5 (MANI - 210.1

Example 20

Z-chlorobenzo SHII, 7|Inaphthyridin-5-amine

MN"

M Moy - Mr

Stage 1: 5-bromo-2-chloropyridine 1-oxide

To a solution of 5-bromo-2-chloropyridine (1.0 equiv.) in chloroform (0.38 M) was added 7795 meta-chloroperbenzoic acid (pSRBA) (4.0 equiv.) and heated at 602C for 20 hours. After cooling to room temperature, Ca(OH)" (5.3 eq.) was added, and the resulting precipitate was stirred for 30 minutes. This precipitate is filtered and washed with a 3:1 CHCl/methanol mixture.

The filtrate is concentrated in vacuo to give a solid which is stirred in 30 95 ethyl acetate in hexane and filtered to give the desired M-oxide. The filtrate is concentrated in a vacuum, and the residue is purified using SOMVIBRGABNOY! system (IZSO), using 0-100 95 ethyl acetate in hexane, which leads to obtaining a larger amount of the desired

M-oxide. The two batches are combined and transferred to the next stage.

Stage 2: 3-bromo-b-chloropicolinonitrile

Trimethylsilyl cyanide (TM5CM) (4.0 equiv) and triethylamine (3 .0 equiv.). The reaction mixture is heated at 1002C overnight. After cooling to room temperature, the solvent is concentrated in vacuo, and the residue is purified using a SOMVIRGAZNO system (IZSO) using 0-40 95 ethyl acetate in hexane to give 3-bromo-6b-chloropicolinonitrile.

Stage 3: Z-Chlorobenzo DP, 7|Inaphthyridin-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq) and 3-bromo-6-chloropicolinonitrile (from step 2) (1.0 eq) in toluene (0.44 M) is mixed with tetrakis(triphenyl - phosphine)palladium (5 mol) and a 2M aqueous solution of potassium carbonate (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMVIBGABZNFO system (IZSO) using 0-50 95 ethyl acetate in hexane to give a solid, which is then triturated in 10 95 ethyl acetate in hexane to give 3-chlorobenzo| DY, 7|Inaphthyridine-

B-amen "H NMR (acetone a-6): b 9.10 (y, 1H), 8.45 (a, 1H), 7.89 (y, 1H), 7.58-7.65 (t, 2H) , 7.35-7.39 (aa, 1H), 6.67 (ri, 2H). And AM5 (MANI - 230.1

Example 21

M, MZ-dimethylbenzo|PC1, YInaphthyridine-3,5-diamine

MN" I 2 | Mody MH. - d

A solution of 3-chlorobenzo|(D(I1,7UInaphthyridin-5-amine (Example 20)) (1.0 equiv.) is dissolved in 40 95 aqueous dimethylamine (0.26 M) and heated in a microwave reactor at 1002C for 30 minutes.

The reaction mixture is concentrated in vacuo, and the residue is purified with the help of the SOMVIRGAZNO system (IZSO) using 0-90 95 ethyl acetate in hexane, which leads to the production of MZ, MZ-dimethyl-benzo(ShP, Yainanaphthyridine-3,5-diamine. "H NMR (methanol a-4): b 8.63 (y, 1H), 8.20 (a, 1Hn), 7.55 (a, 1Hn), 7.A1-7.45 (aa, 1), 7 ,29-7.33 (ad, 1H), 7.27 (9, 1H), 3.26 (z, 6H). And AM5 |(M-NO - 239.1

Example 22

MZ-butylbenzo|C1,7|Inaphthyridine-3,5-diamine

МН» H 2 | We wash -

A solution of 33-chlorobenzoic acid, 7|Inaphthyridin-5-amine (Example 20) (1.0 equiv.) is dissolved in n-butylamine (0.1 M) and heated at 1102C overnight. The reaction mixture is concentrated in vacuo, and the residue is purified using the SOMBIRI AZNO system (IZSO) using 0-90 90 ethyl acetate in hexane to give M3-butylbenzo CP, 7|Inaphthyridine-3,5-diamine. "H NMR (methanol a-4): b 8.42 (a, 1H), 8.13 (9, 1), 7.53 (a, 1), 7.38-7.42 (da, 1n) , 7.25-7.29 (aa, 1n), 6.96 (4, 1H), 3.48 (y, 2H), 1.63-1.71 (t, 2H), 1.43-1 .52 (t, 2H), 0.99 (i, ZN). GG AM5 |MA-NI - 2672

Example 23

Z-vinylbenzo ЧЙ, 7У|Inaphthyridin-5-amine

MN"

M | Can -

A solution of 3-chlorobenzo|Sh/1,7|naphthyridine-5-amine (Example 20) (1.0 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane ( 1.2 equiv.), tetrakistriphenylphosphine)palladium (5 mol) and a 2M aqueous solution of potassium carbonate (2.0 equiv.) in a mixture of toluene/ethanol (4:1, 0.1 M) are heated to 1002C and stirred during the night After cooling to room temperature, the contents of the reaction mixture were diluted with ethyl acetate and water. The two phases are separated, and the aqueous layer is extracted three times with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Mo95O4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-50 96 ethyl acetate in hexane, which gives a solid, which is then triturated in 10 95 ethyl acetate in hexane, which gives 3-vinylbenzo|DI, 7inaphthyridin-5-amine. "H NMR (acetone a-6): b 8.99 (y, 1H), 8.42 (a, 1H), 8.01 (a, 1H), 7.53-7.62 (t, 2H) , 7.30-7.35 (aa, 1H), 7.03-7.10 (aa, 1n), 6.77 (ri, 2H), 6.56 (a, 1H), 5.66 (a , 1H). G AM5 (MANI - 222.1

Example 24

Z-ethylbenzo|ЦІ1, Yanaftyridin-5-amine

MN"

M | As: d

To the solution of Z-vinylbenzo| 10 95 wt. palladium on charcoal (0.2 equiv.). Hydrogen gas is introduced via a balloon, and the reaction mixture is stirred overnight. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in a vacuum, providing 3-ethylbenzo DP, 7-Naphthyridin-5-amine as a white solid. "H NMR (acetone a-6): b 8.93 (y, 1H), 8.41 (a, 1), 7.76 (a, 1), 7.61 (ad, 1), 7.51 -7.55 (aa, 1H), 7.30-7.34 (aa, 1H), 6.55 (ri, 2H), 6.03 (9, 2H), 1.41 (her, ЗН). GAM5 (MANI - 224.1

Example 25

Z-fluorobenzoic acid, 7-Naphthyridin-5-amine

to me

M | ME -

A solution of 3-chlorobenzosTP, 7|Inaphthyridin-5-amine (Example 20) (1.0 equiv.), potassium fluoride (3.0 equiv.), and 18-crown-b (0.2 equiv.) in M- methylpyrrolidone (MMP) (0.4 M) is heated in a microwave reactor at 2102C for 80 minutes. After cooling to room temperature, the crude reaction mixture was purified by HPLC using 10-50 90 acetonitrile in water to afford 3-fluorobenzo| DI, 7|naphthyridine-5-amine. "H NMR (acetone a-6): b 11.40 (Bg, 2H), 9.38-9.42 (aa, 1H), 8.60 (a, 1H), 7.89-7.92 ( ad, 1H), 7.81-7.83 (t, 2H), 7.59-7.66 (t, 1H). And AM5 (MANI - 214.1

Example 26 2-(trifluoromethyl)benzo|(D(I1,7|Inaphthyridin-5-amine

MN"

MU | M» ah 4 Svz

Stage 1: C-chloro-5-(trifluoromethyl)picolinaldehyde oxime

A solution of 3-chloro-5-(trifluoromethyl)picolinaldehyde (1.0 equiv.), hydroxylamine hydrochloride (5.0 equiv.), and pyridine (4.0 equiv.) in ethanol was heated to 952°C and stirred for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water.

The organic layer is washed with saline solution, water, dried over anhydrous MdzoO»4, and concentrated in a vacuum, which leads to obtaining a solid substance, which is transferred to the next stage without additional purification.

Stage 2: 3-chloro-5-(trifluoromethyl)upicolinonitrile

A solution of 3-chloro-5-(trifluoromethyl)picolinaldehyde oxime (1.0 eq.) and Burgess reagent (Vygde55 geadepO) (1.5 eq.) in tetrahydrofuran (0.5 M) is heated to 652C and stirred for 1 hour.

The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer is washed with water, saline solution, dried over anhydrous Mo5o", and concentrated in a vacuum, which leads to obtaining a solid substance, which is transferred to the next stage without additional purification.

Stage 3: 2-(trifluoromethyl)benzo OR, 7|naphthyridin-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq.) and 3-chloro-5-(trifluoromethyl)picolinonitrile (from step 2) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-

phosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMBIGAZNO system (IZSO) using 0-50905 ethyl acetate in hexane to give /-2-(trifluoromethyl)benzo| CI, 7|naphthyridine-5-amine. "H NMR (acetone a-6): b 9.44 (5, 1H), 9.20 (5, 1H), 8.65-8.63 (9, 1H), 7.70-7.61 ( t, 2H), 7.44-7.36 (t, 1H), 6.84 (g, 2H). AND AM5 IM-NI - 264.2

Example 27 2-methoxybenzo| DI, 7|naphthyridine-5-amine

MN"

M Me s yo

Stage 1: C-chloro-5-methoxypicolinonitrile

To a solution of 3,5-dichloropicolinonitrile (1.0 equiv.) in dimethylformamide (DMF) (0.5 M) is added sodium methoxide (1.5 equiv.) and heated to 752С. After stirring for 14 hours, the reaction mixture was diluted with ethyl acetate and water. The organic layer is washed with saturated aqueous Mansoze three times, with water twice, dried over anhydrous Mod5O»4, and concentrated in vacuo.

The crude residue was purified by the SOMBIRGAB system (I5CO) using 15 95 ethyl acetate in hexane to give a mixture of two methoxy regioisomers, one of which is the desired product. This mixture is transferred to the next stage without additional purification.

Stage 2: 2-methoxybenzo DI, 7|naphthyridine-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq.) and 3-chloro-5-methoxypicolinonitrile (from step 1) (1.0 eq.) in toluene (0.44 M) is mixed with tetrakis( triphenylphosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMBIGAZNO system (IZSO) using 50-10095 ethyl acetate in hexane, which gives /--2-methoxybenzo| DI, 7|naphthyridine-5-amine.

Example 28 2-(benzyloxy)benzo DP, 7|Inaphthyridin-5-amine

MN"

M | Me sh -4 OVp

Stage 1: 3-(benzyloxy)-5-bromopyridine

A solution of 5-bromopyridin-3-ol (1.0 equiv.), benzyl bromide (1.2 equiv.), and silver carbonate (1.3 equiv.) in toluene (0.1 M) is heated to 502C and stirred within 18 hours. After cooling to room temperature, the reaction mixture was filtered, eluting with ethyl acetate. The filtrate is concentrated in vacuo to a residue, which is purified using the SOMVIRGAZNO system (IZSO) using 20 95 ethyl acetate in hexane, which gives 3-(benzyloxy)-5-bromopyridine.

Stage 2: 3-(benzyloxy)-5-bromopyridine 1-oxide

A solution of 3-(benzyloxy)-5-bromopyridine (from step 1) (1.0 equiv) and meta-chloroperbenzoic acid (pCPBA) (4.0 equiv) in dichloromethane (0.1 M) was stirred at room temperature for 18 hours.

The reaction is quenched with a saturated aqueous solution of ManHsCO3 and extracted three times with dichloromethane.

The combined organic phases are dried over anhydrous Mod5O".4 and concentrated in vacuo. The crude residue is purified using the SOMVIRSGABNO system (I5CO) using 0-100 95 ethyl acetate in hexane to give 3-(benzyloxy)-5-bromopyridine 1-oxide.

Stage 3: 5-(benzyloxy)-3-bromopicolinonitrile

To a solution of 53-(benzyloxy)-5-bromopyridine 1-oxide (from stage 2) (1.0 equiv.) in acetonitrile (0.2 M) is added trimethylsilyl cyanide (TM5SM) (4.0 equiv.) and triethylamine (3.0 eq.). The reaction mixture is heated at 1002C overnight. After cooling to room temperature, the solvent is concentrated in vacuo, and the residue is purified using a SOMVIRGA system (SOM) using 0-40 95 ethyl acetate in hexane to give a mixture of two benzoxy regioisomers, one of which is the desired product. This mixture is transferred to the next stage without additional purification.

Stage 4: 2-(benzyloxy)benzo| 1, 7|naphthyridine-5-amine

A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 5-(benzyloxy)-3-bromopicolinonitrile (from step 3) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis (triphenylphosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture is heated to 1002C and stirred overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with 2 95 methanol in dichloromethane and water. The two phases were separated and the aqueous layer was extracted twice with 2 96 methanol in dichloromethane. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude product is purified by flash chromatography on a SOMBIBGABZNFFO system (IZSO) using 50-10095 ethyl acetate in hexane to give -2-(benzyloxy)benzo| DI, 7|naphthyridine-5-amine. "H NMR (acetone 4-6): b 8.36 (5, 1H), 7.86 (5, 1H), 7.59-7.56 (a, 2H), 7.46-7.42 ( aa, 2H), 7.40-7.37 (a, 1Hn), 7.20-7.15 (da, 1n), 7.12-7.09 (a, 1n), 6.88-6, 86 (a, 1), 6.77-6.73 (ai, 1H), 5.51 (5, 2H), 4.74 (ri, 2H). GAM5 IMANNI - 3023.

Example 29 2-vinylbenzo ЧЙ, 7У|Inaphthyridin-5-amine

MN"

M | y: xx yo

Stage 1: C-chloro-5-vinylpicolinonitrile

A solution of 3,5-dichloropicolinonitrile (1.0 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.0 equiv.), tetrakis(triphenyl-phosphine)palladium (5 moles), and a 2M aqueous solution of sodium carbonate (3.4 equiv.) in a mixture of toluene/ethanol (2:11, 0.04 M) is stirred at 952C overnight. After cooling to room temperature, the contents of the reaction mixture were diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude material is purified by flash chromatography on a SOMBIRGAZNO system (IZBSO) using 0-80 95 ethyl acetate in hexane to give a white solid.

Stage 2: 2-vinylbenzo | DI, 7UInaphthyridin-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq.) and 3-chloro-5-vinylpicolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol) , and a 2M aqueous solution of sodium carbonate (2.0 eq.) in toluene/ethanol (2:11, 0.03 M) was stirred at 10020 overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMVIRGABNFO system (IZSO) using 0-80 95 ethyl acetate in hexane to give 2-vinylbenzo| CI, 7|naphthyridine-5-amine as a yellow solid. "N

NMR (methanol-a4 - SOCI3): b 8.87 (y, 1H), 8.69 (a, 1H), 8.28 (9, 1H), 7.49-7.58 (t, 2H) , 7.32 (a, 1H), 6.90 (aa, 1n), 6.09 (a, 1H), 5.54 (a, 1). And eM5 (MANI - 2221.

Example 30 2-ethylbenzo|CI1, Yanaftyridin-5-amine

I am 7 Moss with d

10 95 wt. of palladium on charcoal (0.2 equiv.) is added to a solution of 2-vinylbenzo|(SHI1,7|naphthyridine-5-amine (Example 29) in a mixture of ethyl acetate/methanol (14, 0.05 M). Gaseous of hydrogen is introduced by balloon, and the reaction mixture is stirred for 3 hours. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and purified with

SOMBIRSABNOE system (IZSO), using 0-80 905 ethyl acetate in hexane, which leads to the receipt of 2-ethylbenzoD(1,7|Inaphthyridin-5-amine in the form of a solid. "H NMR (methanol-ad): b 8.78 -8.81 (t, 2H), 8.45 (a, 1H), 7.55-7.63 (t, 2H), 7.35-7.40 (t, 1H), 2.97 (a , 2H), 1.43 (her, 2H). And AM5 (MANI - 2241.

Example 31 2-phenylbenzo|C1, YInaphthyridin-5-amine

Me we mo

Stage 1: C-chloro-5-phenylpicolinonitrile

A solution of 3,5-dichloropicolinonitrile (1.0 equiv.), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (1.0 equiv.), tetrakis(triphenyl-phosphine)palladium (5 moles), and a 2M aqueous solution of sodium carbonate (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 1002C for 2 hours, then at 802 for 4 hours. After cooling to room temperature, the contents of the reaction mixture were diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M95O5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO), using 0-80 9o ethyl acetate in hexane, which gives a white solid.

Stage 2: 2-phenylbenzo|CY1,7|naphthyridine-5-amine

A solution of /2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq.) and 3-chloro-5-phenylpicolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 moles) , and a 2M aqueous solution of sodium carbonate (2.0 eq.) in toluene/ethanol (2:11, 0.03 M) was stirred at 10020 overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude product is purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give 2-phenylbenzo|C1,7Inaphthyridine-5-amine as a white solid. "N

NMR (DMSO-4c): b 9.13 (y, 1H), 9.03 (a, 1H), 8.56 (y, 1Hn), 7.98 (a, 2H), 7.43-7, 56 (t, 5H), 7.27 (t, 1H), 7.13 (rz, 2H). And AM5 (MANI - 272.2.

Example 32 (E)-2-styrylbenzo DI, 7|naphthyridine-5-amine

Mn

MU M a

Stage 1: (E)-3-chloro-5-styrylpicolinonitrile

A solution of 3,5-dichloropicolinonitrile (1.0 equiv.), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (1.0 equiv.), tetrakis(triphenyl -phosphine)palladium (5 mol), and a 2M aqueous solution of sodium carbonate (3.4 equiv.) in a toluene/ethanol mixture (2:1, 0.04 M) is stirred at 1002C for 2 hours, then at 8020 for 4 hours . After cooling to room temperature, the contents of the reaction mixture were diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous M95O.:, and concentrated in vacuo. The crude product is purified by flash chromatography on a SOMVIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give a white solid .

Stage 2: (E)-2-styrylbenzo DY, 7|naphthyridine-5-amine

A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 equiv.) and (E)-3-chloro-5-styrylpicolinonitrile (from step 1) (1.0 equiv.), tetrakis(triphenylphosphine)palladium ( 5 molbb), and a 2M aqueous solution of sodium carbonate (2.0 eq.) in toluene/ethanol (2:11, 0.03 M) was stirred at 10020 overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude product was purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to afford (E)-2-styrylbenzo DCP, 7|Inaphthyridin-5-amine as a brown solid. "H NMR (DMSO-α): b 9.22 (y, 1H), 9.06 (a, 1H), 8.51 (a, 1H), 7.78 (a, 1Hn), 7.66 ( a, 2H), 7.46-7.56 (t, ЗН), 7.70 (1, 2H), 7.26-7.32 (t, 2H), 7.08 (rev, 2H). I AM5 |MA-NI - 298.2.

Example 33 2-phenethylbenzo|DI1,7|naphthyridin-5-amine

to me

We are

Add 10 95 wt. palladium on charcoal (0.2 equiv.). Hydrogen gas is introduced via a balloon, and the reaction mixture is stirred for 3 hours. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and the crude product is purified by flash chromatography on a SOMBIRGAZNO) system (IZSO) using 0-80 95 ethyl acetate in hexane, which gives 2-phenethyl-benzo|ЦІ1, 7|Inaphthyridin-5-amine as yellow solid. "H NMR (SOSI"): b 8.54 (y, 1H), 8.32 (a, 1Hn), 8.10 (aa, 1Hn), 7.63 (aa, 1H), 7.51 (t , 1H), 7.03-7.32 (t, 6H), 6.16 (p5, 2H), 3.11 (her, 2H), 2.97 (, 2H). AND AM5 |M-NI - 300.1.

Example 34 (E)-2-(3-methoxyprop-1-enylubenzo DP, 7|Inaphthyridin-5-amine

МНь sa: с | Dn

Stage 1: (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile

A solution of 3,5-dichloropicolinonitrile (1.0 equiv.), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,9,2-dioxaborolane (1, 0 equiv.), tetrakis(triphenylphosphine)palladium (5 molbb), and a 2M aqueous solution of sodium carbonate (3.4 equiv.) in a mixture of toluene/ethanol (2:1, 0.04 M) are stirred at 1002C for 2 hours, then at 802C for 4 hours. After cooling to room temperature, the contents of the reaction mixture were diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Ma5O»4, and concentrated in vacuo. The crude product is purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile as a white solid matter.

Stage 2: (E)-2-(3-Methoxyprop-1-enyl/benzo CHY, 7|Inaphthyridin-5-amine

A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 equiv) and (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile (from step 1) (1.0 equiv) , tetrakis(triphenylphosphine)palladium (5 moles), and a 2M aqueous solution of sodium carbonate (2.0 equiv.) in toluene/ethanol (2:1, 0.03 M) were stirred at 1002C overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude product is purified by flash chromatography on a SOMBIRGAB system (I5CO) using 0-80 95 ethyl acetate in hexane to give (E)-2-(3-methoxyprop-1-enyl)benzo ЧІ1,7|naphthyridine-5 -amine as a yellow solid. "H NMR (DMSO-α): b 9.24 (y, 1H), 9.18 (a, 1), 8.54 (a, 1H), 7.52-7.58 (t, 2H), 7.91 (t, 1H), 7.11 (p5, 2H), 6.86-7.00 (t, 2H), 4.18 (a, 2H), 3.36 (5, ЗН). I AM5 | MANI - 266.2.

Example 35 2-(3-methoxypropyl)benzo OR, 7|Inaphthyridin-5-amine

Me again ak: xx | - unit

To a solution of (E)-2-(3-methoxyprop-1-enyl)/benzo|DY1,7U-naphthyridin-5-amine (Example 34) in a mixture of ethyl acetate/methanol (1:4, 0.05 M) add 10 95 mass . palladium on charcoal (0.2 equiv.). Gaseous hydrogen is injected using a balloon, and the reaction mixture is stirred for 3 hours. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and the crude product is purified by flash chromatography on a SOMVIRGAS system (IZSO) using 0-8095 ethyl acetate in hexane to give /-2-(3-methoxypropyl)benzo| (1, 7|Inaphthyridin-5-amine in the form of a white solid. "H NMR (SOCI"): b 8.64 (a, 1H), 8.46 (a, 1H), 8.19 (a, 1Hn ), 7.66 (a, 1H), 7.53 (t, 1H), 7.91 (t, 1H), 6.56 (p5, 2H), 3.37 (Her, 2H), 3.91 (in, ZN), 2.91 (i, 2H), 1.93-2.00 (t, 2H). GAM5 IM-ANI - 268.1.

Example 36 2-(prop-1-en-2-ilubenzo DP, 7|Inaphthyridin-5-amine

Mne pen: with | dp

Step 1: C-chloro-5-(prop-1-en-2-yl)picolinonitrile

A solution of 33,5-dichloropicolinonitrile (1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.0 equiv. .), tetrakis(triphenyl-phosphine)palladium (5 moles), and a 2M aqueous solution of sodium carbonate (3.4 equiv.) in a mixture of toluene/ethanol (2:1, 0.04 M) are stirred at 1002C for 2 hours, then at 802C for 4 hours. After cooling to room temperature, the contents of the reaction mixture were diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Moa5O»4, and concentrated in vacuo. The crude product is purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give 3-chloro-5-(prop-1-en-2-yl)picolinonitrile as a white solid .

Stage 2: 2-(prop-1-en-2-ylubenzo(DI, 7|naphthyridine-5-amine

A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloro-5-(prop-1-en-2-yl)picolinonitrile (from step 1) (1.0 eq.), tetrakistriphenyl -phosphine)palladium (5 moles), and a 2M aqueous solution of sodium carbonate (2.0 eq.) in toluene/ethanol (2:11, 0.03 M) was stirred at 10020 overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude product is purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give 2-(prop-1-en-2-yl)benzo(7)inaphthyridin-5-amine in in the form of a white solid. "H NMR (DMSO-α): b 9.03 (y, 1H), 8.96 (y, 1H), 8.55 (a, 1H), 7.47-7.53 ( t, 2H), 7.25 (t, 1H), 7.07 (rz, 2H), 5.80 (5, 1H), 5.36 (v, 1H), 2.27 (z, ЗН). I AM5 I(M-NO - 236.2.

Example 37 2-isopropylbenzo|(ЦІ1,7|naphthyridin-5-amine

Mn

M M s | d

10 95 wt of palladium on charcoal (0.2 eq.) Hydrogen gas is introduced via balloon and the reaction mixture is stirred for 3 hours. This mixture is filtered through a Celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and the crude product is purified by flash chromatography on a SOMVIRGAS system (IZSO), using 0-80 95 ethyl acetate in hexane, which leads to the receipt of 2-isopropyl-benzo DP, 7-Naphthyridin-5-amine as a yellow solid. "H NMR (SOCI"): b 8.69 (a, 1),

8.49 (a, 1H), 8.25 (ad, 1H), 7.65 (ad, 1), 7.53 (t, 1H), 7.91 (t, 1H), 6.02 (p5 , 2H), 3.15 (zero, 1H), 1.37 (a, 6H). And AM5 (MANI - 238.2.

Example 38 1-methylbenzoic acid, 7|Inaphthyridin-5-amine

Mnh aa: s -

Stage 1: 5-bromo-2-chloro-4-methylpyridine 1-oxide

A solution of 5-bromo-2-chloro-4-methylpyridine (1.0 eq.) and meta-chloroperbenzoic acid (tCPBA) (2.5 eq.) in chloroform (0.1 M) was stirred at 502C overnight. After cooling to room temperature, Ca(OH)» (2.5 eq.) was added to the reaction mixture. The precipitate is filtered and washed with 5 95 methanol in dichloromethane and ethyl acetate. The filtrate is washed with a saturated aqueous Magn52Oz solution and a saturated aqueous ManHsSoOz solution. The combined organic phases are washed with brine, dried over anhydrous M950O", and concentrated in vacuo to a pale solid, which is carried to the next stage without additional purification.

Stage 2: 3-bromo-b-chloro-4-methylpicolinonitrile

TM5CM (4.0 equiv) and triethylamine (3, 0 eq.). The reaction mixture is heated at 1002C overnight. After cooling to room temperature, the solvent is concentrated in vacuo, and the residue is purified by SOMBIRI AZNO system (IZSO) using 0-50 90 ethyl acetate in hexane to give 3-bromo-6-chloro-4-methylpicolinonitrile.

Stage 3: 3-Chloro-1-methylbenzo CHY, 7|Naphthyridin-5-amine

A solution of 2-(tert-butoxycarbonylamino)uphenylboronic acid (1.0 eq.) and 3-bromo-6b-chloro-4-methylpicolinonitrile (from step 2) (1.0 eq.), tetrakis(triphenylphosphine)palladium ( 5 molbb), and a 2M aqueous solution of sodium carbonate (2.0 eq.) in toluene/ethanol (2:11, 0.03 M) was stirred at 10020 overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude product is purified by flash chromatography on a SOMVIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give 3-chloro-1-methyl-benzo SHI, 7|Inaphthyridin-5-amine as a white solid . "H NMR (DMSO-α): 5 8.44 (a, 1H), 7.83 (5, 1H), 7.50-7.58 (t, 2H), 7.02 (65, 2H), 2.98 (in, ZN).

IGAM5 MANI - 2441.

Stage 4: 1-MethylbenzoShP, 7|Inaphthyridin-5-amine

10 95 wt. is added to a solution of /Z-chloro-1-methylbenzo|CI,/|Inaphthyridin-5-amine (from stage 3) in a mixture of ethyl acetate/methanol (1:2, 0.03 M). palladium on charcoal (0.2 equiv.). The reaction vessel was shaken in a hydrogen steamer at 50 psi of hydrogen overnight. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and purified using a SOMBIRSABB system (I5CO) using 0-80 90 ethyl acetate in hexane to give 1-methylbenzo SHI, 7|Inaphthyridin-5-amine as a white solid. "N

NMR (SOSI): b 8.63 (a, 1H), 8.44 (y, 1H), 7.71 (aa, 1H), 7.54 (t, 1H), 7.45 (a, 1H ), 7.30 (t, 1H), 6.20 (65, 2H), 3.01 (5, ЗН). And AM5 | MANI - 210.1.

Example 39 benzo|c|/1,8|Inaphthyridine-6b-amine

MN"

Mm xx ba

A solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)/pyridin-2-ylcarbamate (1.0 eq.) and 2-bromobenzonitrile (1.0 eq.), tetrakis(triphenylphosphine)palladium (5 mol), and a 2M aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) were stirred at 1002C overnight.

After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude product is purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give benzoic acid/1,8-inaphthyridine-b-amine as a white solid. "H NMR (methanol-adai): b 8.88 (da, 1H), 8.67-8.63 (t, 2H), 8.30 (a, 1), 7.90 (a, 1), 7.74 (a 1), 7.36 (aa, 1H).

GAM5 MANI - 196.1

Example 40 pyridoZ3,2-PCP, /|naphthyridine-6-amine

MN"

M Me

MO 4 -

A solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)/pyridin-2-ylcarbamate (1.0 eq.) and 3-bromopicolinonitrile (1.0 equiv.), tetrakis(triphenylphosphine)palladium (5 moles), and a 2M aqueous solution of sodium carbonate (2.0 equiv.) in toluene/ethanol (2:1, 0.03 M) were stirred at 1002C overnight.

After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid is filtered off and the filtrate is concentrated in vacuo to give a crude residue. The crude product is purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give pyridoyi3,2-Cy1,7|inaphthyridine-b-amine as a white solid. "N

NMR (DMSO-α): b 9.14 (aa, 1H), 68.98 (ad, 1Hn), 68.90 (aa, 1H), 7.93 (aa, 1H), 7.60 (65, 2H), 7.30 (yes, 1Hn).

IGAM5 MANI - 197.

Example 41 2-ethyl-8-methylbenzo DI, 7|Inaphthyridin-5-amine

Mn,

M 2 xx

Stage 1: 8-methyl-2-vinylbenzo H(1,7|naphthyridine-5-amine

A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenyl-carbamate (with

of Example 5/Stage 2) (1.0 eq.) and 3-chloro-5-vinylpicolinonitrile (from Example 29 / Stage 1) (1.0 eq.), tetrakis(triphenylphosphine)palladium (5 molbobo), and A 2M aqueous solution of sodium carbonate (2.0 equiv.) in a mixture of toluene/ethanol (2:1, 0.03 M) is stirred at 1002C overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid was filtered off, and the filtrate was concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMVIBABNFOYA system (IZSO) using 0-80 90 ethyl acetate in hexane to give 8-methyl-2-vinylbenzoDP, 7-Naphthyridin-5-amine as a yellow solid.

Stage 2: 2-ethyl-8-methylbenzo H/1,7|naphthyridin-5-amine

Add 10 95 wt. palladium on charcoal (0.2 equiv.). Gaseous hydrogen is injected using a balloon, and the reaction mixture is stirred for 3 hours. This mixture was filtered through a Celite filter and washed with dichloromethane. The filtrate is concentrated in vacuo and purified using a SOMBIRI AZNO system (IZSO) using 0-80% ethyl acetate in hexane to give 2-ethyl-8-methylbenzo|SHI, 7-Naphthyridin-5-amine as an off-white solid . "H NMR (SOSI"): b 8.61 (y, 1H), 8.42 (a, 1H), 8.10 (a, 1H), 7.44 (5, 1H), 7.12 (da , 1H), 6.00 (p5, 2H), 2.84 (9, 2H), 2.45 (5, ZN), 1.33 (I, ZN). And AM5 (MANI - 238.1.

Example 42 (5-amino-8-methylbenzo|DY, 7|Inaphthyridin-2-yl)methanol

MH,

M 2

Heh ON

Stage 1: Ethyl 5-chloro-6-cyanonicotinate

A solution of ethyl 5,6-dichloronicotinate (1 equiv.), zinc cyanide (0.75 equiv.) and tetrakis(triphenylphosphine)palladium (0.10 equiv.) in DMF (0.3 M) is degassed and then heated at 100 "C for 3 hours. The solvent is removed in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMBIRGAB system (I5CO) using 0-80 95 ethyl acetate in hexane to give ethyl 5-chloro-b- Cyanonicotinate as a white solid.

Stage 2: Ethyl 5-amino-8-methylbenzo|ЦІ1, 7ІInaphthyridine-2-carboxylate

A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate (with

of Example 5 /stage 2) (1.0 equiv.) and ethyl 5-chloro-b-cyanonicotinate (from the previous stage) (1.0 equiv.), tetrakis(triphenylphosphine)palladium (5 molbb), and 2M aq. a solution of sodium carbonate (2.0 equiv.) in a mixture of toluene/ethanol (2:1, 0.03 M) is stirred at 1002C overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid was filtered off, and the filtrate was concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMBIBABNFOY system (IZSO) using 0-80 95 ethyl acetate in hexane to give ethyl 5-amino-8-methylbenzoSHII1,7|Inaphthyridine-2-carboxylate.

Stage 3: 2-ethyl-8-methylbenzo H/1,7|naphthyridin-5-amine

Add ethyl 5-amino-8-methylbenzo| to the stirred solution To 1,7U of naphthyridine-2-carboxylate (from the previous stage) in THF (0.2 M), cooled in an ice-water bath, add a 1 M solution of perhydride in THF (10 equiv.). After the end of the reaction, the reaction is quenched with 1 M Na, and extracted with EtOAc. The combined organic extracts are concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMVIRG AZNF system (IZSO) using 0-80 90 ethyl acetate in hexane, which gives (5-amino-8-methylbenzoxy, 7|Inaphthyridin-2-yl)umethanol in the form of a white solid matter. "H NMR (SOCIz"): b 8.68 (ad, tn), 8.52 (9, 1), 8.04 (y, 1H), 7.44 (5, 1H), 7.12 (aa , 1H), 6.00 (65, 2H), 4.90 (in, 2H), 2.45 (z, ЗН). I VM5

IMANNI - 240.1

Example 43 8-methyl-2-propylbenzo|(ЦІ1,7|naphthyridin-5-amine

MN.

M s xx

Stage 1: (E)-3-chloro-5-(prop-1-enyl)picolinonitrile

A solution of 3,5-dichloropicolinonitrile (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-(prop-1-enyl)-1,3,2-dioxaborolane (1.0 eq. .), tetrakis(triphenyl-phosphine)palladium (5 molUb), and a 2M aqueous solution of sodium carbonate (3.4 equiv.) in a mixture of toluene/ethanol (2:11, 0.04 M) are stirred at 95 "C overnight .

After cooling to room temperature, the contents of the reaction mixture were diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

MBO", and concentrated in a vacuum to obtain a crude residue. The crude material was purified by flash chromatography on a SOMBIRGAB system (I5CO) using 0-80 95 ethyl acetate in hexane to give (E)-3-chloro-5-(prop-1-enyl)picolinonitrile as a white solid.

Stage 2: (E)-8-methyl-2-(prop-1-enyl/benzo DI, 7-naphthyridin-5-amine

A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)uphenyl carbamate (with

of Example 5 / Stage 2) (1.0 equiv.) and (E)-3-chloro-5-(prop-1-enyl)-picolinonitrile (from the previous stage) (1.0 equiv.), tetrakis(triphenyl- phosphine)palladium (5 moles), and a 2M aqueous solution of sodium carbonate (2.0 eq.) in a mixture of toluene/ethanol (2:11, 0.03 M) is stirred at 1002C overnight. After cooling to room temperature, the contents of the reaction mixture are diluted with methanol. The insoluble solid was filtered off, and the filtrate was concentrated in vacuo to give a crude residue.

The crude material is purified by means of flash chromatography on a SOMBIGAZNO system (IZSO), using 0-80 95 ethyl acetate in hexane, which leads to obtaining (E)-8-methyl-2-(prop-1-enyl)-benzo DP, 7UInaphthyridine- 5-amine as a yellow solid.

Stage 3: 8-methyl-2-propylbenzo|DI1, 7YInaphthyridin-5-amine

To a solution of (E)-8-methyl-2-(prop-1-enyl)/benzo|DI1,7|naphthyridin-5-amine (from the previous stage) in a mixture of ethyl acetate/methanol (1:4, 0.05 M ) add 10 95 wt. palladium on charcoal (0.2 equiv.). Hydrogen gas is introduced via a balloon, and the reaction mixture is stirred for 3 hours. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and purified using a SOMVIRI AZNO system (IZSO) using 0-80% ethyl acetate in hexane to give 8-methyl-2-propylbenzo(P,7|naphthyridine-5-amine) as an off-white solid substance. "H NMR (SOSI"): b 8.59 (y, 1H), 8.41 (a, 1H), 8.10 (y, 1), 7.43 (5, 1H), 7, 13 (ai, 1H), 5.94 (p, 2H), 2.78 (I, 2H), 2.44 (5, ЗН), 1.75 (t, 2Н), 0.95 (I, ЗН ). And AM5 (MANI - 252.1

Example 44 2-(2-(1H-indol-5-yl)ethyl)-8-methylbenzo H(1,7|naphthyridin-5-amine

MH,

M 2 and hundred

MN

Stage 1: 5-(triethylsilyl)ethynyl)-1H-indole

-iodo-1H-indole (1.1 eq.), triethyl(ethynyl)sylan (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M) are added to a scintillation tube. Vacuum and irrigate with nitrogen three times. They add

Si! (0.1 equiv.) and bis(triphenylphosphine)dichloropalladium(II) (0.1 equiv.). The tube is sealed and heated at 60°C overnight. After the TLC-monitored reaction is complete, the contents of the tube are transferred to a silica column pretreated with hexanes. The column is washed with hexanes and diethyl ether, collecting all product-containing eluents. Hexanes and ether are carefully removed using a rotary evaporator with minimal heating, which provides the product 5-(triethylsilyl)ethynyl)-1H-indole as a colorless oil, which is carried directly to the next stage.

Stage 2: 5-ethynyl-1H-indole

To a stirred solution of 5-(triethylsilyl)ethynyl)-1H-indole (from the previous stage) in THF (0.2

M), cooled at 0 "C, is treated dropwise with a solution (0.5 equiv) of tetrabutylammonium fluoride. The reaction mixture turns black and is continued to stir for 30 minutes before warming to room temperature. TLC shows complete conversion. The reaction is quenched with water and extracted with diethyl ether.The combined organic phases were dried over anhydrous

Ma?5O4 and concentrate using a rotary evaporator with minimal heating.

Chromatography (silica gel, diethyl ether) provides the product 5-ethynyl-1H-indole in the form of a colorless oil.

Step 3: 5-(1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile

5-ethynyl-1H-indole (from the previous step) (1.1 eq.), 3,5-dichloropicolinonitrile (1 eq.), triethylamine (5 eq.), and anhydrous DMF ( 0.2 M). Vacuum and irrigate with nitrogen three times. Si (0.05 equiv.) and bis(triphenylphosphine)dichloropalladium(I!) (0.05 equiv.) are added. The membrane is replaced with an irrigation refrigerator and the flask is heated at 60 °C overnight in a nitrogen atmosphere. After the reaction, which is monitored by TLC, the contents of the flask are transferred to a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EOAc (1: 4 95)) leads to the product 5-((1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile.

Stage 4: 2-(1H-indol-5-yl)ethynyl)-8-methylbenzo|(C(1,7|naphthyridin-5-amine

5-(1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile (from the previous stage) (1 equiv), tert-butyl 2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolane-2-iluphenylcarbamate (from Example 5 / Step 2) (125 equiv.), KzPOi.(2 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv.), and 2-dicyclohexylphosphino-2",b'-dimethoxybiphenyl (0.1 equiv). n-butanol and water (5:2, 0.2 M) are added, and the contents are degassed (after the vacuum is flushed with nitrogen) three times. The reaction mixture stirred vigorously in a nitrogen atmosphere at 100 "C overnight in an oil bath. The contents were cooled and transferred to 200 ml of water, followed by extraction with methylene chloride. The combined organic phases were dried (Mag5054) and concentrated. Flash chromatography

(silica gel, 0-5095 EMUOAc in СНоСи") provides the product 2-((1H-indol-5-yl)ethynyl)-8-methylbenzo H/1,7|Inaphthyridin-5-amine in the form of a yellow solid.

Stage 5: 2-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-8-methylbenzo|DI1,7|naphthyridine-5-amine

In a round-bottomed flask, add 2-(1H-indol-5-yl)/ethynyl)-1-methyl-benzoSTP, 7|Inaphthyridin-5-amine (from the previous stage) (1 equiv.) with a magnetic stirrer. Ethanol and methylene chloride (122.02 g) are added, followed by palladium on charcoal (activated powder, mild, 10 95 on charcoal, 0.1 eq.). The contents are vacuumed, and then irrigated with hydrogen three times. The reaction mixture was stirred vigorously under a hydrogen cylinder at room temperature overnight. After that, the reaction mixture is filtered through a Celite filter, and the Celite filter is washed successively with methylene chloride and EIOAc until the absorbance of the filtrate in the UV region disappears. The combined organic washing waters are concentrated. Flash chromatography (silica gel, 0-5095 EOAc in SNegSiIg) provides the product 2-(2-(2,3- dihydrobenzofuran-5-yl)ethyl)-8-methyl-benzo| SCI, 7|naphthyridine-5-amine as a yellow solid. "H NMR (SOSIv): b 8.54 (y, 1H), 8.34 (a, 1H), 8.28 (5, 1H), 7.99 (a, 1H), 7.64-7, 56 (t, 1H), 7.50-7.35 (t, 1H), 7.24 (a, 1), 7.12 (I, 1), 7.08 (ad, 1n), 6.92 (ad, 1H), 6.41 (5, 1H), 6.01 (p5, 2H), 3.16-3.12 (t, 2H), 3.10-3.05 (t, 2H), 2.43 (5, ZN). And AM5 IM.ANI - 353.2

Example 45 2-(4-ethoxyphenethyl)-8-methylbenzotrisyl, 7|Inaphthyridin-5-amine kn, 7 2 sa ol»

Stage 1: 3-chloro-5-((4-ethoxyphenyl)ethynyl)picolinonitrile

1-Ethoxy-4-ethynylbenzene (1.1 equiv.), 3.5-dichloropicolinonitrile (1 equiv.), triethylamine (5 equiv.), and anhydrous DMF (0.2 M) are added to a round-bottomed flask closed with a membrane. . Vacuum and irrigate with nitrogen three times. Add Si! (0.05 equiv.) and bis(triphenylphosphine)dichloropalladium(II) (0.05 equiv.). The membrane is replaced with an irrigation refrigerator and the flask is heated at 60 °C overnight in a nitrogen atmosphere. After the reaction, which is monitored by TLC, the contents of the flask are transferred to a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes: EtOAc (1: 4 90)) provides the product of 3-chloro-5-((4-ethoxyphenyl)ethynyl)picolinonitrile.

Stage 2: 2-((4-Ethoxyphenyl)ethynyl)-H-methylbenzo CHY, 7-Naphthyridin-5-amine

3-Chloro-5-((4-ethoxyphenyl)ethynyl)picolinonitrile (from the previous stage) (1 equiv.), tert-butyl 5-methyl-2-(4,4,5,5 - tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate (from Example 5 / Stage 2) (1.25 eq.), KzPOx (2 eq.), tris(idibenzylideneacetone)dipalladium(0) (0, 05 eq.), and 2-dicyclohexylphosphino-2",6'-dimethoxybiphenyl (0.1 eq.). Add n-butanol and water (5:2, 0.2 M), and the contents are degassed (after vacuum, flush with nitrogen ) three times. The reaction mixture is stirred vigorously under nitrogen at 100 C overnight in an oil bath. The contents are cooled and transferred to 200 mL of water followed by extraction with methylene chloride. The combined organic phases are dried (Ma?»5O4) and concentrated. Flash chromatography (silica gel, 0-5095 BESCHOAc in СНоСи») provides the product 2-((4-ethoxyphenyl)ethynyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine.

Stage 3: 2-(4-ethoxyphenethyl)-8-methylbenzo CP, 7|Inaphthyridin-5-amine

2-((4-Ethoxyphenyl)ethynyl)-8-methyl-benzo|CI1,N-naphthyridin-5-amine (from the previous step) (1 eq.) is added to a round-bottomed flask with a magnetic stirrer. Add ethanol and methylene chloride (122.02 mM), followed by palladium on charcoal (activated powder, wet, 10 95 on charcoal, 0.1 eq.). The contents are degassed in a vacuum, and then irrigated with nitrogen (three times). The reaction mixture is vigorously stirred under a hydrogen cylinder at room temperature overnight. After that, the reaction mixture is filtered through a Celite filter, and the Celite filter is washed successively with methylene chloride and EtOAc until the absorbance of the filtrate in the UV region disappears. The combined organic washing waters are concentrated. Flash chromatography (silica gel, 0-50 96 EUAs in SNeoSig) provides the product as a yellow solid. Further recrystallization using toluene provides the product 2-(4-ethoxyphenethyl)-8-methylbenzo|D(1,7|naphthyridin-5-amine) in the form of white finely dispersed crystals. "H NMR (SOCI"): b 8.52 (a, 1H), 8.30 (a, 1H), 8.10 (a, 1H), 7.46 (5, 1H), 7.12 (aa, 1h), 7.06 (a, 2H) , 6.75 (a, 2H), 5.95 (65, 2H), 3.93 (d, 2H), 3.11-3.05 (da, 2H), 2.95-2.90 (ad , 2H), 2.44 (5, ZN), 1.33 (I, ZN). I AM5 IM--NO - 358.2

Example 46 8-methyl-2-(4-phenoxyphenethyl)benzol

M 2 ev o

Stage 1: 3-chloro-5-((4-phenoxyphenyl)ethynyl)picolinonitrile

C-Chloro-5-((4-phenoxyphenyl)ethynyl)picolinonitrile is prepared from /1-ethynyl-4-phenoxy-benzene (commercially available) following the procedures described for Example 45, step 1.

Stage 2: 8-methyl-2-((4-phenoxyphenyl)ethynyl)benzo| DY, 7|naphthyridin-5-amine 8-Methyl-2-((4-phenoxyphenyl)ethynyl)benzo| 1, 1Naphthyridine-5-amine is prepared from 333-chloro-5-((4-phenoxyphenyl)ethynyl)picolinonitrile (from the previous step) following the procedures described for

Example 45, stage 2.

Stage 3: 8-Methyl-2-(4-phenoxyphenethyl)benzo|ЦІ1, 7ІNaphthyridin-5-amine 8-Methyl-2-(4-phenoxyphenethyl)benzo|D/І1, 7ІNaphthyridin-5-amine is obtained from /8- methyl-2-((4-phenoxyphenyl)ethynyl)benzo CI, 7|Inaphthyridin-5-amine (from the previous step), following the procedures described for Example 45, step 3. "H NMR (SOCI"): b 8, 54 (y, 1H), 8.30 (y, 1H), 8.01 (y, 1H), 7.45 (5, 1H), 7.25-7.20 (t, 2H), 7.12 (yes, 1H), 7.07-6.84 (t, 8H), 6.00 (p5, 2H), 3.13-3.08 (09, 2H), 2.99-2.94 (yes , 2H), 2.44 (5, ZN). AND AM5 |M-NI - 406.2

Example 47 2-(2,4-dimethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine

Mn,

M 2 more

Step 1: (2,4-Dimethylphenyl)ethynyl)triethylsilane ((2,4-Dimethylphenyl)ethynyltriethylsilane was prepared from 1-iodo-2,4-dimethylbenzene (commercially available) following the procedures described for Example 44, Step 1.

Step 2: 1-Ethynyl-2,4-dimethylbenzene 1-Ethynyl-2,4-dimethylbenzene was prepared from (2,4-dimethylphenyl)ethynyl)utriethylsilane (from the previous step) following the procedures described for Example 44, step 2.

Stage 3: 3-chloro-5-(2,4-dimethylphenyl)ethynyl)picolinonitrile

C-Chloro-5-(2,4-dimethylphenyl)ethynyl)picolinonitrile is prepared from 1-ethynyl-2,4-dimethylbenzene (from the previous step) following the procedures described for Example 44, step 3.

Stage 4: 2-((2,4-Dimethylphenyl)ethynyl)benzo CI, 7|Naphthyridin-5-amine 2-(2,4-Dimethylphenyl)ethynyl)/benzo CI, 7|Naphthyridin-5-amine is obtained from Z Z -chloro-5-((2,4-dimethylphenyl)ethynyl)-picolinonitrile (from the previous step), following the procedures described for

Example 44, stage 4.

Stage 5: 2-(2,4-dimethylphenethyl)benzo DI, 7|naphthyridine-5-amine 2-(2,4-Dimethylphenethyl)benzo CH, 7|naphthyridine-5-amine is obtained from 2-(2,4- dimethylphenyl)ethynyl)benzo| DY, 7|naphthyridine-5-amine (from previous step) following the procedures described for Example 44, step 5. "H NMR (SOCI"): b 8.60 (a, 1H), 8.33 (a, 1H), 8.14 (a, 1H), 7.67 (a, 1H), 7.54 (, 1H), 7.91 (I, 1H), 6.96-6.86 (t, ЗН) , 6.29 (p5, 2H), 3.04-3.10 (aa, 2H), 2.97-2.91 (ad, 2H), 2.24 (5, ЗН), 2.20 (5 , ZN). AND AM5 |MA-NI - 328.2.

Example 48 2-(2,4-dimethylphenethyl)-8-methylbenzo|ЦІ1, 7ІNaphthyridin-5-amine

MH,

M 2 more

Stage 1: 2-(2,4-dimethylphenyl)ethynyl)-8-methylbenzo|DI1,7|naphthyridin-5-amine

2-(2,4-Dimethylphenyl)ethynyl)-H-methylbenzo CY, 7|Inaphthyridin-5-amine is obtained from 3-chloro-5-(2,4-dimethylphenyl)ethynyl)picolinonitrile (from Example 47 / Stage 3) and tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate) (from Example 5 / Step 2) following the procedures described for Example 44, stage 4.

Stage 2: 2-(2,4-Dimethylphenethyl)-8-methylbenzo(ЦІ1,7|naphthyridin-5-amine 2-(2,4-Dimethylphenethyl)-8-methylbenzo DI, 7|naphthyridin-5-amine is obtained from of 1-ethynyl-4-phenoxybenzene (from the previous step), following the procedures described for Example 44, step 5." H

NMR (SOSI): b 8.56 (a, 1H), 8.28 (a, 1H), 8.00 (a, 1H), 7.46 (5, 1H), 7.14 (da, 1H ), 6.95-6.85 (t, ZN), 6.26 (rz, 2H), 3.08-3.02 (aa, 2H), 2.96-2.90 (da, 2H), 2.45 (in, ZN), 2.23 (5, ZN), 2.19 (5, ZN). AND AM5 IM.ANI - 342.2

Example 49 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo C(1,7|naphthyridin-5-amine

Mn,

M hl che o7

Stage 1: 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile

C-Chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile is prepared from 1-ethynyl-4-methoxy-2-methylbenzene (commercially available) following the procedure described for Example 44 / Step 3.

Stage 2: 2-((4-Methoxy-2-methylphenyl)ethynyl)-8-methylbenzo DY, 7Inaphthyridin-5-amine 2-(4-Methoxy-2-methylphenyl)ethynyl)-8-methylbenzo(ЦІ1,7| Naphthyridin-5-amine is prepared from 3-chloro-5-(4-methoxy-2-methylphenethyl)picolinonitrile (from the previous step) following the procedures described for Example 44, step 4.

Stage 3: 2-(4-Methoxy-2-methylphenethyl)-8-methylbenzol/I1,7uInaphthyridin-5-amine 2-(4-Methoxy-2-methylphenethyl)-8-methylbenzo C(1,7|Inaphthyridin-5 -amine is prepared from 2-((4-methoxy-2-methylphenyl)ethynyl)-8-methylbenzo|C(1,7Inaphthyridin-5-amine (from the previous step) following the procedures described for Example 44, step 5. H NMR (SOCI"): b 8.53 (a, 1H), 8.29 (y, 1H), 8.01 (a, 1H), 7.44 (5, 1H), 7.12 (aa, 1H), 6.93 (a, 1H), 6.67 (a, 1H), 6.60 (ad, 1), 5.93 (p5, 2H), 3.70 (5, ЗН), 3, 05- 3.00 (aa, 2Hn), 2.93-2.88 (ad, 2H), 2.44 (v, ЗН), 2.19 (5, ЗН). I AM5 |M-NI - 358 ,2

Example 50 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3-methylphenol

MN, the ball" also he

To a stirred solution of 2-(4-methoxy-2-methylphenethyl)-8-methyl-benzoSHI,7|naphthyridin-5-amine (Example 49) in methylene chloride (0.2 M) in an ice-water bath, add 1 M solution of ВВгз (2 eq.) in

SneaSig by drop method. After 30 minutes, the reaction was quenched with methanol and concentrated in vacuo to give a crude residue. The crude material is purified by means of flash chromatography on a SOMVIRG AN system (IZSO) using 0-20 95 methanol in dichloromethane, which leads to 4-(2-(5-amino-Y-methylbenzo (DY, 7|naphthyridine-2- yl)ethyl)-3-methylphenol in the form of a white solid. "H NMR (DMSO-α): b 8.99 (5, 1Н), 8.75 (0, 1Н), 8.60 (а, 1Н) , 8.27 (a, 1H), 7.28 (5, 1H), 7.09 (ad, 1H), 6.99 (rz, 2H), 6.88 (a, 1H), 6.49 ( a, 1H), 6.42 (aa, 1H), 3.02-2.96 (aa, 2H), 2.86-2.81 (ad, 2H), 2.38 (5, ЗН), 2 ,13 (5, ZN). AND AM5 |MA-NI - 344 2

Example 51 2-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-8-methylbenzo| DI, 7UInaphthyridin-5-amine

MH,

M 2 hundred (6;

Step 1: (2,3-Dihydrobenzofuran-5-yl)ethynyl)utriethylsilane ((2,3-Dihydrobenzofuran-5-yl)uethynylutriethylsilane is prepared from 5-iodo-2,3-dihydrobenzofuran (commercially available) following the procedures, described for Example 44, stage 1.

Step 2: 5-Ethynyl-2,3-dihydrobenzofuran 5B-Ethynyl-2,3-dihydrobenzofuran is prepared from ((2,3-dihydrobenzofuran-5-yl)ethynyl)-triethylsilane (from the previous step) following the procedures described for Example 44 / Stage 2.

Stage 3: 3-chloro-5-(2,3-dihydrobenzofuran-5-yl)ethynyl)picolinonitrile

C-Chloro-5-((2,3-dihydrobenzofuran-5-yl)ethynyl)picolinonitrile is prepared from 5-ethynyl-2,3-dihydrobenzofuran (from the previous step) following the procedures described for Example 44 / Step

WITH.

Stage 4: 2-((2,3-dihydrobenzofuran-5-yl)ethynyl)-8-methylbenzo| 1, 7-Naphthyridin-5-amine 2-(2,3-Dihydrobenzofuran-5-yl)ethynyl)-Y-methylbenzo CY, 7|Naphthyridin-5-amine is obtained from 3-chloro-5-(4-methoxy-2- methylphenethyl)picolinonitrile (from the previous step), following the procedures described for Example 44 / Step 4.

Stage 5: 2-(2-(2,3-Dihydrobenzofuran-5-yl)ethyl)-8-methylbenzo|DI1,7|naphthyridin-5-amine 2-(2-(2,3-Dihydrobenzofuran-5-yl) )ethyl)-8-methylbenzo CY, 7-Naphthyridin-5-amine is obtained from 2-((2,3- dihydrobenzofuran-5-yl)ethynyl)-8-methylbenzo| CI, 7|Inaphthyridine-5-amine (from the previous step), following the procedures described for Example 44 / Step 5. "H NMR (SOCI"): b 8.62 (y, 1H), 8.40 (a, 1H), 8.11 (y, 1H), 7.53 (5, 1H), 7.21 (da, 1H), 6.99 (5, 1H), 6.95 (ad, 1nH), 6, 74 (a, 1H), 6.05 (p5, 2H), 4.57 (i, 2H), 3.19-3.13 (t, 4H), 3.03-2.98 (aa, 2H) , 2.54 (5, ZN). AND AM5 |MA-NI - 356.2

Example 52 2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)ethanol

MN

M | y: 4 on

Step 1: (2)-3-Chloro-5-(2-ethoxyvinyl)picolinonitrile (2)-3-Chloro-5-(2-ethoxyvinyl)picolinonitrile is prepared from (2)-2-(2-ethoxyvinyl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane (commercially available), following the procedures described for Example 43 /

Stage 1.

Stage 2: (7)-2-(2-ethoxyvinyl)-1-methylbenzo DI, 7|naphthyridine-5-amine (27)-2-(2-Ethoxyvinyl)-81-methylbenzo DI, 7|naphthyridine-5- amine is prepared from (2)-3-chloro-5-(2-ethoxyvinyl)picolinonitrile (from the previous step) following the procedures described for Example 43 /

Stage 2.

Stage 3: 2-(5-amino-8-methylbenzo|CI1, 7YInaphthyridin-2-yl)ethanol

A solution of (2)-2-(2-ethoxyvinyl)-Y-methylbenzo 1, 7|naphthyridine-5-amine (from the previous stage) in a mixture of 2:5 conc. HCl and dioxane (0.1 M) are heated at 60 °C overnight. After cooling to room temperature, the reaction mixture is treated with an excess of ManHsCO3 saturated solution, followed by extraction with EOAc. The combined organic extracts are concentrated and transferred to THF (0 .2 M), and treated with a 1 M solution of superhydride in THF (10 equiv.) at 0 "C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture is processed following the procedures described for Example 42 / Stage 3, which provides 2-(5-amino-8-methylbenzo|DI,7|naphthyridin-2-yl)ethanol as a white solid. "H NMR (SOSI"): b 8.61 (y, 1H), 8.47 (a, 1H), 8.01 (a, 1H), 7.41 (5, 1H), 7.10 (a , 1H), 6.40 (5, 1H), 6.01 (65, 2H), 4.01 (I, 2H), 3.06 (i, 2H), 2.43 (5, ЗН). I AM5 | M. ANI - 254.1

Example 53

3-methyl-9-phenyl-9,10-dihydrobenzo | Pfuroi(2,3-511,7|naphthyridine-6b-amine

MH,

Her OS

Step 1: 5-Bromo-2-chloro-3-methylpyridine 1-oxide 5B-Bromo-2-chloro-3-methylpyridine 1-oxide is prepared from 5-bromo-2-chloro-3-methylpyridine (commercially available) following procedures described for Example 19 / Stage 1.

Stage 2: 3-bromo-b-chloro-5-methylpicolinonitrile

3-Bromo-6-chloro-5-methylpicolinonitrile is prepared from (2)-3-chloro-5-(2-ethoxyvinyl)-picolinonitrile (from the previous step) following the procedures described for Example 19 / Step 2.

Step 3: 3-bromo-b-chloro-5-(2-hydroxy-2-phenylethyl)picolinonitrile

A solution of 3-bromo-b-chloro-5-methylpicolinonitrile (from the previous stage) in THF (0.2 M) is cooled to -78°C. GOA (2M solution, 2 equiv.) is added dropwise. The reaction mixture is continued to be stirred at -78 "C for 1 hour, accompanied by the addition of benzaldehyde (1 equiv.).

The reaction mixture was continued to stir at -78°C for an additional 30 minutes before being allowed to slowly cool to room temperature. The reaction was quenched with sat.

MNACI and extracted with EIUAs. The combined organic washing waters are concentrated. Flash chromatography (silica gel, 20-50 95 EIOAc in hexanes) provides the product 3-bromo-6b-chloro-5-(2-hydroxy-2-phenylethyl)picolinonitrile as a yellow solid.

Stage 4: 3-methyl-9-phenyl-9,10-dihydrobenzo|Cfuro(2,3-511,7|naphthyridine-6b-amine

3-Methyl-9-phenyl-9,10-dihydrobenzo|Pfuro(2,3-511,7|naphthyridine-b-amine is obtained from 3-bromo-6-chloro-5-methylpicolinonitrile (from the previous step) following the procedures , described for Example 44 / Stage 4. "H NMR (SOCI"): b 8.45 (c, 1H), 7.98 (j, 1H), 7.45 (c, 1H), 7.40-7 ,28 (t, 5H), 7.12 (9, 1H), 5.93 (I, 1H), 5.93 (riv, 2H), 3.86 (ai, 1H), 3.40 (ad, 1H), 2.44 (5, ZN). And AM5 (MANI - 328.1

Example 54 8-methylbenzo| DI, 7|naphthyridine-2,5-diamine

Mn,

M | and: 4 Mn,

Stage 1: tert-butyl 5,6-dichloropyridin-3-ylcarbamate

To a solution of 5,6-dichloropyridin-3-amine (commercially available) in THF (0.2 M) is stirred at 07 and (BOC) 2 O (1.2 equiv.) is added. The reaction mixture is heated at 40 "C until complete conversion, which is controlled by TLC. The reaction mixture is then concentrated. Flash chromatography (silica gel, 20-50 95 BESHCOAc in hexanes) of the crude product allows obtaining tert-butyl 5,6-dichloropyridine-3- ylcarbamate.

Stage 2: tert-butyl 5-chloro-6-cyanopyridin-3-ylcarbamate

Tert-butyl 5-chloro-6-cyanopyridin-3-ylcarbamate is prepared from tert-butyl 5,6-dichloropyridin-3-ylcarbamate (from the previous step) following the procedures described for Example 42 / Step 1.

Stage 3: 8-methylbenzo DP, 7-Naphthyridine-2,5-diamine 8-methylbenzo| DI, 7|Naphthyridin-2,5-diamine is obtained (as a minor product) together with tert-butyl 5-amino-8-methylbenzo CHI, 7|Naphthyridin-2-ylcarbamate (as the main product) from tert-butyl 5-chloro -6- cyanopyridin-3-ylcarbamate (from the previous step), following the procedures described for Example 5 /

Stage 2. "H NMR (DMSO-4v): b 10.11 (5, 1H), 9.02 (5, 1H), 8.82 (4, 1H), 8.06 (y, 1H), 7 .34 (5, 1H), 7.15 (aa, 1H), 6.99 (5, 2H), 2.44 (v, ZN). AND AM5 MANI - 225.1

Example 55 1-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)propan-2-ol

MH,

M 2

For him

Stage 1: 3-bromo-5-methylpicolinonitrile

C3-Bromo-5-methylpicolinonitrile is prepared from 2,3-dibromo-5-methylpyridine (commercially available) following the procedures described for Example 42 / Step 1.

Step 2: 3-bromo-5-(2-hydroxypropyl)picolinonitrile

3-Bromo-5-(2-hydroxypropyl)picolinonitrile is prepared from 3-bromo-5-methylpicolinonitrile (from the previous step) and acetaldehyde following the procedures described for Example 53 / Step 3.

Stage 3: 1-(5-amino-8-methylbenzo|CPI1, 7UInaphthyridin-2-ylpropan-2-ol 1-(5-Amino-8-methylbenzo|DY1,7|naphthyridin-2-yl)upropan-2- ol was prepared from 3-bromo-5-(2-hydroxypropyl)picolinonitrile (from the previous step) following the procedures described for Example 53, step 4. "H NMR (methanol-da): b 8.72 (a, 1H) , 8.68 (a, 1H), 8.24 (j, 1), 7.38 (5, 1H), 7.18 (da, 1h), 4.16-4.07 (t, 1H), 3.05-2.99 (t, 2H), 2.97-2.90 (t, 2H), 2.47 (5, ZN), 1.28 (a, ZN). HeM5 IM.ANI - 268 ,1

Example 56 2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)acetonitrile

MH,

M y: r dm

Stage 1: 2,3-dichloro-5-((methoxymethoxy)methyl)pyridine

Triethylamine (3 equiv.) and chloro(methoxy)methane (2 equiv.) are added to a stirred solution of (5,6-dichloropyridin-3-yl)umethanol (commercially available) in CNeSi (0.2 M) at 0 °C. After stirring at 0 "C for 3 hours, the reaction mixture is concentrated and the crude product is purified by chromatography (silica gel, 20-5095 EtOAc in hexanes), which provides 2,3-dichloro-5-((methoxymethoxy)methyl)pyridine in the form colorless oil.

Step 2: 3-chloro-5-((methoxymethoxy)methyl)picolinonitrile

C-Chloro-5-(methoxymethoxy)methyl)picolinonitrile is prepared from 2,3-dichloro-5-((methoxymethoxy)methyl)pyridine (from the previous step) following the procedures described for

Example 42 / Stage 1.

Stage 3: 3-chloro-5-(hydroxymethyl)picolinonitrile

To a stirred solution of 2,3-dichloro-5-((methoxymethoxy)methyl)pyridine (from the previous stage) in methanol (0.2 M) add conc. NSI (10 equiv.). After stirring at room temperature overnight, the reaction mixture is concentrated in vacuo and the resulting crude product is purified by chromatography (silica gel, 20-50 95 EIOAc in hexanes) to afford 3-chloro-5-(hydroxymethyl)picolinonitrile.

Stage 4: 3-chloro-5-(chloromethyl)picolinonitrile

To a stirred solution of 3-chloro-5-(hydroxymethyl)picolinonitrile (from the previous stage) in

Thionyl chloride (10 eq.) is added to SNeSig (0.2 M) at 0"C. After stirring at room temperature overnight, the reaction mixture is concentrated in vacuo and the resulting crude product is purified by chromatography (silica gel, 20-50 95 EOAc in hexanes), which ensures the production of 3-chloro-5-(chloromethyl)picolinonitrile in the form of a colorless oil.

Stage 5: 3-chloro-5-(cyanomethyl)picolinonitrile

Sodium cyanide (1.25 eq.) is added to a solution of 3-chloro-5-(chloromethyl)picolinonitrile (from the previous step) in DMSO (0.2 M). The reaction mixture is heated at 130 "C under microwave irradiation.

The reaction mixture is transferred to water and EtOAc, and extracted with EtOAc. The organic phases are dried over anhydrous Mag5O»4 and concentrated. Flash chromatography (silica gel, 20-50 96 EUAs in hexanes) of the crude product provides the preparation of 3-chloro-5-(cyanomethyl)picolinonitrile.

Stage 6: 2-(5-amino-8-methylbenzo|CI1, 7-Naphthyridin-2-yl)acetonitrile 2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)acetonitrile is obtained from Z-chloro -5-(cyanomethyl)picolinonitrile (from the previous step), following the procedures described for Example 44 /

Stage 4. "H NMR (methanol-α): b 8.79 (a, 1H), 8.78 (a, 1H), 8.20 (a, 1H), 7.66 (5, 2H), 7 .36 (5, 1H), 7.18 (aa, 1H), 4.15 (d, 2H), 2.43 (z, ZN). AND AM5 IMANI - 249.1

Example 57

M-(5-amino-8-methylbenzo|DC(1,7|Inaphthyridin-2-yl)lacetamide

MH,

CA

M

Nn

Stage 1: M-(5,6-dichloropyridin-3-yl)luacetamide

Acetyl chloride (2 equiv.) is added to a stirred solution of 5,6-dichloropyridin-3-amine (commercially available) and triethylamine (3 equiv.) in CH2SO4 (0.2 M) at 0 °C. After stirring at at room temperature overnight, the reaction mixture is concentrated in vacuo and the resulting crude residue is purified by chromatography (silica gel, 20-50 95 EOAc in hexanes), which provides M-(5,6-dichloropyridin-3-yl)acetamide.

Stage 2: M-(5-Chloro-6-cyanopyridin-3-yl)acetamide

M-(5-chloro-6-cyanopyridine-3-yl)acetamide is prepared from (5,6-dichloropyridin-3-yl)acetamide (from the previous step) following the procedures described for Example 42 / Step 1.

Stage 3: M-(5-amino-8-methylbenzo DP, 7|Inaphthyridin-2-yl)acetamide

M-(5-amino-8-methylbenzo|D(1,7|Inaphthyridin-2-ylluacetamide) is prepared from M-(5-chloro-6-cyanopyridin-3-ylluacetamide) (from the previous step) following the procedures described for Example 44 / Stage 4. "NN

NMR (DMSO-α): 6 10.99 (5, 1H), 8.18 (a, 1H), 8.95 (a, 1H), 8.12 (9, 1H), 7.44 (5, 1H), 7.35 (ai, 1H), 2.43 (5,

ZN), 2.16 (5, ZN). And AM5 | MANI - 267.1

Example 58 2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)-1-(2,4-dimethylphenyl)ethanol

MN

Ma | he etc

Stage 1: 3-bromo-5-(2-(2,4-dimethylphenyl)-2-hydroxyethyl)picolinonitrile

3-Bromo-5-(2-(2,4-dimethylphenyl)-2-hydroxyethyl)picolinonitrile was prepared from 3-bromo-5-methylpicolinonitrile (Example 55 / Step 1) and 2,4-dimethylbenzaldehyde following the procedures described for Example 53 / Stage 3.

Stage 2: 2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)-1-(2,4-dimethyl-phenyl)-ethanol 2-(5-Amino-8-methylbenzo |C(1,7|naphthyridin-2-yl)-1-(2,4-dimethylphenyl)ethanol is obtained from 3-bromo-5-(2-(2,4-dimethylphenyl)-2-hydroxyethyl)picolinonitrile (from previous stage), following the procedures described for Example 53 / Stage 4. "H NMR (SOCI"): b 8.67 (y, 1H), 8.45 (a, 1H), 8.06 (y, 1H) , 7.57 (5, 1H), 7.42 (a, 1), 7.23 (9, 1), 7.11 (a, 1), 7.01 (5, 1H), 5.31 ( ad, 1H), 3.28-5.25 (t, 2H), 2.53 (5, ZN), 2.35 (5, ZN), 2.33 (5, ZN). AND AM5 IMA-NI - 358.2

Example 59 2-(2-(6-methoxy-4-methylpyridin-3-yl)ethyl)-8-methylbenzo| DI, 7UInaphthyridin-5-amine

MH,

M 2 korzh de oi

MT

Stage 1: 2-Methoxy-4-methyl-5-(triethylsilyl)ethynyl)pyridine 2-Methoxy-4-methyl-5-(triethylsilyl)ethynyl)pyridine is obtained from 5-bromo-2-methoxy-4-methylpyridine (commercial available), following the procedures described for Example 44 / Stage 1.

Step 2: 5-Ethynyl-2-methoxy-4-methylpyridine 5-Ethynyl-2-methoxy-4-methylpyridine is prepared from 2-methoxy-4-methyl-5-(triethylsilyl)ethynyl)pyridine (from the previous step) following procedures described for Example 44 / Stage 2.

Step 3: 3-chloro-5-((b-methoxy-4-methylpyridin-3-yl)ethynyl)picolinonitrile

C-Chloro-5-((6-methoxy-4-methylpyridin-3-yl)ethynyl)picolinonitrile is prepared from 5-ethynyl-2-methoxy-4-methylpyridine (from the previous step) following the procedures described for Example 44 / Stage 3.

Stage 4: 2-((b-Methoxy-4-methylpyridin-3-yl)/ethynyl)-8N-methyl-benzo|DI1,7N-naphthyridin-5-amine 2-(6-Methoxy-4-methylpyridin-3 -yl)/ethynyl)-H-methylbenzo OR, 7|naphthyridin-5-amine is obtained from 3-chloro-5-((6-methoxy-4-methylpyridin-3-yl)ethynyl)picolinonitrile (from the previous stage), following the procedures described for Example 44 / Stage 4.

Stage 5: 2-(2-(b-Methoxy-4-methylpyridin-3-yl)ethyl)-8-methylbenzo|ЦИ1, 7|Inafthyridin-5-amine 2-(2-(6-Methoxy-4 -methylpyridine-3-yl)ethyl)-8-methylbenzo| 1, 7U|Inaphthyridin-5-amine is obtained from 2-((b-methoxy-4-methylpyridin-3-ylethynyl)-8-methylbenzo DI, 7Inaphthyridin-5-amine (from the previous step), following the procedures described for Example 44 / Stage 5. "H NMR (SOCI"): b 8.65 (a, 1H), 8.43 (90, 1H), 8.13 (a, 1), 7.87 (c, 1H ), 7.57 (5, 1H), 7.24 (aa, 1H), 6.60 (5, 1H), 6.39 (p5, 2H), 3.91 (v,

ZN),3.17-3.11 (ad, 2H), 3.03-2.98 (aa, 2H), 2.54 (5, ZN), 2.28 (5, ZN). And AM5 IM-NI - 359.2

Example 60 4-(4-(2-(5-amino-8-methylbenzo| 1, 7| naphthyridin-2-yl) ethyl) phenyl) butan-1-ol

Mn,

M | and: ON

CO

Stage 1: 4-(4-(trimethylsilyl)ethynyl)phenyl)but-3-yn-1-ol 4-(4-(trimethylsilyl)ethynyl)uphenyl)but-3-yn-1-ol is obtained from ((4 -bromophenyl)ethynyl)trimethylsilane (commercially available) and but-3-yn-1-ol (commercially available) following the procedures described for Example 44 / Step 1.

Step 2: 4-(4-Ethynylphenyl)but-3-yn-1-ol 4-(4-ethynylphenyl)but-Z-yn-i-sl is obtained from 4-(4-(trimethylsilyl)ethynyl)/phenyl) of but-3-yn-1-ol, following the procedures described for Example 44 / Step 2.

Stage 3: 5-((4-(4-hydroxybut-1-ynyl)phenyl)ethynyl)-3-methylpicolinonitrile 5-((4-(4-hydroxybut-1-ynyl)phenyl)ethynyl)-3-methylpicolinonitrile is obtained with 4-(4-ethynylphenyl)but-

of Z-yn-1-ol (from the previous step), following the procedures described for Example 44 / Step 3.

Stage 4: 4-(4-((5-amino-1-methylbenzo DY, 7|naphthyridin-2-yl)ethynyl)uphenyl)but-2-yn-1-ol 4-(4-((5-amino -8-methylbenzo|(DI1,7|naphthyridin-2-yl)ethynylphenyl)but-2-yn-1-ol is obtained from 5-((4-(4-hydroxybut-1-ynyl)uphenyl)ethynyl)-Z -methylpicolinonitrile (from the previous step), following the procedures described for Example 44 / Step 4.

Stage 5: 4-(4-(2-(5-amino-8-methylbenzo| (1, 7-Naphthyridin-2-yl)ethyl)phenyl)butan-1-ol 4-(4-(2-(5-amino) -8-methylbenzo|Ш/1,7|naphthyridin-2-yl)ethyl)phenyl)butan-1-sl is obtained from 4-(4-((5-amino-8-methylbenzo CI, 7|Inaphthyridin-2- yl)ethynylphenyl)but-2-yn-1-ol (from the previous step), following the procedures described for Example 44 / Step 5. "H NMR (SOCI"): b 8.58 (y, 1H), 8, 36 (a, 1H), 8.07 (9, 1), 7.53 (5, 1H), 7.20 (aa, 1n), 7.10 (aa, 4H), 6.20 (р, 2H ), 3.68 (i, 2H), 3.20-3.15 (aa, 2H), 3.06-3.01 (aa, 2H), 2.64 (I, 2H), 2.52 ( in, ZN), 1.75-1.57 (t, 4H). And AM5 IMANI - 386.2

Example 61 methyl 3-(4-(2-(5-amino-8-methylbenzo|ЦІ1, 7ІNaphthyridin-2-yl)uethyluphenyl)upropanoate

MN

M 2 ac

Fe «h (6;

Stage 1: Methyl 3-(4-iodophenyl)propanoate

To a stirred solution of 3-(4-iodophenyl)propanoic acid (commercially available) in toluene and methanol (9:11, 002 M) 0 "C is added (diazomethyl)utrimethylsilane (1 M solution in ESO, 2 eq.). After stirring. at room temperature overnight, the reaction mixture is concentrated in vacuo and the resulting crude residue is purified by chromatography (silica gel, 20-50 90 EtOAc in hexanes), which provides methyl 3-(4-iodophenyl)propanoate.

Stage 2: Methyl 3-(4-ethynylphenyl)propanoate

Methyl 3-(4-ethynylphenyl)propanoate is prepared from methyl 3-(4-iodophenyl)propanoate (from the previous step) following the procedures described for Example 44 / Steps 1 and 2.

Step 3: Methyl 3-(4-((5-chloro-6-cyanopyridin-3-yl)ethynyl/uphenyl)propanoate

Methyl 3-(4-(5-chloro-6-cyanopyridin-3-yl)ethynylphenylpropanoate is prepared from methyl 3-(4-ethynylphenyl)propanoate (from the previous step) following the procedures described for Example 44 /

Stage 3.

Stage 4: methyl 3-(4-((5-amino-8-methylbenzo| DI, 7-Naphthyridin-2-yl)ethynyl)-phenyl)upropanoate

Methyl 3-(4-(5-amino-1-methylbenzo DY, 7|naphthyridin-2-yl)ethynylphenyl)upropanoate is obtained from methyl 3-(4-((5-chloro-6-cyanopyridin-3-yl)uethynyl /uphenyl)upropanoate (from the previous step), following the procedures described for Example 44 / Step 4.

Stage 5: Methyl 3-(4-(2-(5-amino-1-methylbenzo CY, 7-Naphthyridin-2-yl)ethyl)-phenyl)-propanoate

Methyl 3-(4-(2-(5-amino-8-methylbenzo C(1,7|Inaphthyridin-2-yl)ethyluphenyl)upropanoate is obtained from methyl 3-(4-((5-amino-8-methylbenzo| (D(1,7|naphthyridin-2-yl)ethynyl)u-phenyl)upropanoate (from the previous step), following the procedures described for Example 44 / Step 5. "H NMR (DMSO-a6): b 8.83 (a, 1H), 8.72 (a, 1H), 8.32 (9, 1H), 7.35 (5, 1H), 7.21-7.12 (t, 5H), 7.05 ( Bi 5, 2H), 7.05 (aa, 2H), 3.57 (5, ZN), 3.19-3.13 (aa, 2H), 3.06-3.00 (ad, 2H), 2.81 (her, 2H), 2.60 (her, 2H), 2.45 (z, ZN). AND AM5 |M-ANI - 400.2

Example 62 3-(4-(2-(5-amino-8-methylbenzo| 1, 7| naphthyridin-2-yl) ethyl) phenyl) propan-1-ol

MH,

M | Sche: -dsi СХ on 3-(4-(2-(5-amino-8-methylbenzo|Ш/1,7|naphthyridin-2-yl)ethyl)phenyl)propan-1-ol is obtained from methyl 3- (4-(2-(5-amino-8-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)-phenyl)upropanoate (from Example 61) following the procedures described for Example 42/Stage 3. "H NMR TRA salts: (DMSO-α): b 9.56 (5, 1Н), 9.24 (5, 1Н), 8.92 (а, 1), 8.81 (а, 1Н), 8.43 (а , 1H), 7.44 (a, 1), 7.35 (a, 1H), 7.13 (aa, 2H), 7.05 (aa, 2H), 3.32 (i, 2H), 3 ,18-3.12 (da, 2H), 3.02-2.95 (aa, 2H), 2.50 (I, 2H), 2.44 (5, ЗН), 1.65-1.57 (t, 2H). GAM5 |M-NI - 372.2

Example 63 4-(4-(2-(5-amino-8-methylbenzo| 1, 7|Inaphthyridin-2-yl)ethyl)phenyl)-2-methylbutan-2-ol

MH,

M | M che on

To a solution of methyl 3-(4-(2-(5-amino-1-methylbenzoic acid, 7|inaphthyridin-2-yl)ethyl)-phenyl)propanoate (with

Example 61) in THF (0.2 M) at 0 "С, a solution of methylmagnesium bromide in THF (1.0 M, 2 equiv.) is added dropwise. After stirring at room temperature overnight, the reaction mixture is concentrated in vacuo and the resulting crude residue purified by chromatography (silica gel, 50-100 95 EOAc in hexanes) which ensures the receipt of /4-(4-(2-(5-amino-8- methylbenzo1,7Inaphthyridin-2-yl)lethyl)uphenyl)-2-methylbutane -2-ol. "H NMR (SOSIv): b 8.64 (y, 1H), 8.34 (a, 1H), 8.06 (yh, 1H), 7.57 (a, 1H), 7 ,30-7.20 (t, 2H), 7.18-7.07 (t, 4H), 6.67 (rv, 2H), 3.24-3.16 (aa, 2H), 3.08 -3.01 (ad, 2H), 2.73-2.66 (t, 2H), 2.53 (5, ЗН), 1.82-1.75 (t, 2H), 1.91 (5 , ZN), 1.29 (5, ZN). And VM5

IMANI - 400.2

Example 64 2-(4-(aminomethyl)phenethyl)-8-methylbenzo CI, 7-Naphthyridin-5-amine

Mn,

M | and: - si SA me,

Stage 1: 4-(2-(5-amino-8-methylbenzo|CP1, 7YInaphthyridin-2-yl)ethyl)benzonitrile

4-(2-(5-amino-8-methylbenzo DP, 7-Inaphthyridin-2-yl)ethyl)benzonitrile is prepared from 4-ethynylbenzonitrile (commercially available) following the procedures described for Example 44 / Steps 3-5.

Stage 2: 2-(4-(aminomethyl)phenethyl)-8-methylbenzo DI, 7|Inaphthyridin-5-amine

To a solution of 4-(2-(5-amino-8α-methylbenzo(/1,7|naphthyridin-2-yl)ethyl)benzonitrile (from the previous stage) in ethanol and ammonium hydroxide (4:1, 0.2 M) , stirred at room temperature, Raney nickel (10 eq.) is added. The reaction mixture is stirred under a hydrogen atmosphere until the conversion is complete, as determined by TLC. The reaction mixture is filtered through a short celite filter.

The celite filter is washed with EOAc. The combined organic extracts are concentrated in vacuo and the resulting crude residue is purified by chromatography (silica gel, 50-100 95

EUAs in hexanes) which provides the product /2-(4-(aminomethyl)-phenethyl)-8-methylbenzoxy, 7-Naphthyridin-5-amine. "H NMR TRA salt: (methanol-az): b 8.81 (y, 1H), 8.79 (a, 1H), 8.38 (9, 1H), 7.51 (5, 1H), 7 ,44 (ad, 1), 7.36 (aa, 4H), 4.07 (5, 2H), 3.29 (5, 2H), 3.20-3.14 (da, 2H), 2, 55 (5, ZN).

GAM5 MANI - 343.2

Example 65 (E)-ethyl 3-(4-(2-(5-amino-8-methylbenzo N(1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate

MH,

M 2 what db (6;

Oh and

Stage 1: (4-(2-(5-amino-1-methylbenzo OR, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)-methanol (4-(2-(5-amino-8-methylbenzo | DI, 7|naphthyridin-2-yl)ethyl)-3-methylphenylmethanol is obtained "from methyl /4-(2-(5-amino-8-methylbenzo|(DI1,7|naphthyridin-2-yl)uethyl)- of 3-methylbenzoate (Example 115) following the procedures described for Example 42 / Step 3.

Stage 2: 4-(2-(5-amino-8-methylbenzo|CP1, 7YInaphthyridin-2-yl)ethyl)-3-methyl-benzaldehyde

2-iodoxybenzoic acid ( IVH, 2.5 equiv). The reaction mixture was stirred at room temperature for 3 hours before dilution with water. Extraction with EAc followed by concentration provided a crude residue which was purified by chromatography (silica gel, 50-100 95 EAc in hexanes), which ensures the production of 4-(2-(5-amino-8-methylbenzo|ЦІ1, 7Inaphthyridin-2-yl)ethyl)-3-methylbenzaldehyde.

Stage C: (E)-ethyl 3-(4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate

Ethyl 2-(diethoxyphosphoryl)acetate (commercially available) (3 equiv.) is added to a suspension of Mann (3 equiv) in THF (0.2 M) stirred at 0"C. After stirring for 30 minutes, a solution of 4-(2- (5-amino-d-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)-3-methylbenzaldehyde (from the previous step) in THF (0.2 M) was added dropwise.The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with sat. provides the preparation of (E)-ethyl 3-(4-(2-(5-amino-8-methylbenzo|C(1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate in the form of a white solid. "N

NMR: (SOSI"): 6 8.54 (a, 1H), 8.29 (y, 1H), 7.99 (a, 1H), 7.57 (a, 1H), 7.44 (5, 1H), 7.23 (aa, 1H), 7.11 (aa, 1H), 7.05 (a, 1H), 6.33 (a, 1H), 5.93 (5, 2H), 4, 19 (9, 2H), 3.10-2.95 (t, 4H), 2.44 (5, ЗН), 2.23 (5, ЗН), 1.26 (I, ЗН). GAM (MANI - 426.2

Example 66 Ethyl 3-(4-(2-(5-amino-1-methylbenzo CHY, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)propanoate

Mn,

M 2" schu

FI UK oy rya

Ethyl 3-(4-(2-(5-amino-8-methylbenzo DY, 7N-naphthyridin-2-yl)ethyl)-3-methylphenyl)-propanoate is obtained from (E)-ethyl 3-(4-(2-( 5-Amino-8-methylbenzo SHI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate (from Example 65), following the procedures described for Example 44 / Step 5. "H

NMR: (SOSI"): 6 8.55 (0, 1H), 8.26 (a, 1H), 7.99 (y, 1H), 7.45 (5, 1H), 7.12 (ad, 1H), 6.98-6.88 (t, 3H), 6.02 (5, 2H), 4.06 (ad, 2H), 3.04 (ad, 2H), 2.93 (ad, 2H ), 2.83 (, 2H), 2.53 (I, 2H), 2.44 (5, ЗН), 2.19 (5, ЗН), 1.17 (i,

ZN). AM5 MANI - 428.2

Example 67 2-(4-(2-(5-amino-8-methylbenzo|1, 7|naphthyridin-2-yl)ethyl)-3-methylbenzyl)propane-1,3-diol

Mn,

M y: what

He

Stage 1: diethyl 2-(4-(2-(5-amino-8-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzyl)malonate

To a stirred solution of (4-(2-(5-amino-Y-methylbenzo CHY, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)methanol (from Example 65 / Stage 1) (0.2 M) and of diethyl malonate (2 equiv.) in dry toluene, tributylphosphine (2 equiv.) and M'M',Me,Me-tetramethyldiazene-1,2-dicarboxamide (2 equiv.) are added.

The reaction mixture is stirred at 120 "C overnight. After the end of the reaction, the reaction mixture is concentrated in vacuo and the resulting crude residue is purified by chromatography (silica gel, 50-100 95 EOAc in hexanes), which ensures the receipt of diethyl 2-(4-(2 -(5-amino-8-methyl-benzo DP, 7-Naphthyridin-2-yl)ethyl)-3-methylbenzyl)malonate in the form of a white solid.

Stage 2: 2-(4-(2-(5-amino-8-methylbenzo| (1,7Inaphthyridin-2-yl)ethyl)-3-methylbenzyl)-propane-1,3-diol 2-(4-( 2-(5-Amino-8-methylbenzo CY, 7|naphthyridin-2-yl)ethyl)-3-methylbenzyl)propane-1,3-diol is obtained from diethyl 2-(4-(2-(5-amino- 8-methylbenzo (1,7 |naphthyridin-2-yl)ethyl)-3-methylbenzyl)malonate (from the previous step), following the procedures described for Example 42 /

Stage 3. "H NMR: (methanol-a): b 8.51 (y, 1H), 8.39 (a, 1H), 8.05 (y, 1H), 7.45 (5, 1H), 7.10 (da, 1H), 6.91-6.687 (t, 2H), 6.83 (da, 1), 3.42 (a, 4H), 3.08-3.02 (t, 2H) , 2.96-2.91 (t, 2H), 2.47 (9, 2H), 2.38 (5, ZN), 2.13 (5, ZN). GAM5 IMANNI - 416.2

Example 68 3-(4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyl)-3-methylphenyl)propanoic acid

MH,

M She: dd si SH young o

A solution of ethyl 3-(4-(2-(5-amino-8-methylbenzo[1,7|naphthyridin-2-yl)ethyl)-3-methylphenyl)-propanoate (from Example 66) in 1 M Mahon, tTHF and methanol (1:5:2, 0.1 M) is heated at 60 "C for 3 hours.

After cooling to room temperature, the reaction mixture is neutralized with 1 M HCl to pH 7 and concentrated to give a crude residue, which is purified by chromatography (silica gel, 0-20 95 methanol in dichloromethane), which provides (E) -ethyl 3-(4- (2-(5-amino-8-methylbenzo| DP, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate as a white solid. "H NMR: (methanol-dal): b 8.73 (y, 1H), 8.54 (y, 1H), 8.20 (a, 1H), 7.45 (5, 1H), 7.37 (a, 1H), 7.00- 6.97 (t, 2H), 6.92 (j, 1H), 3.19 (i, 2H), 3.04 (I, 2H), 2.81 ( i, 2H), 2.53 (i, 2H), 2.50 (5, ЗН), 2.25 (5, ЗН).

GAM5 MANI - 400.2

Example 69

B-amino-2-(4-methoxy-2-methylphenethyl)benzo C(1,7|Inaphthyridine-8-carbaldehyde

MN, 7 2 that 7 (6;

B-amino-2-(4-methoxy-2-methylphenethyl)benzo ХІ, 7|Inaftyridine-8-carbaldehyde is obtained from (5-amino-2-(4-methoxy-2-methylphenethyl)benzo|ЦІ1, Ianaftyridine-8 -ilumethanol (from Example 108), following the procedures described for Example 65 / Stage 2. "H NMR: (SOCI"): b 10.19 (5, 1H), 8.74 (y, 1H), 8.43 (a, 1H), 8.32 (a, 1H), 8.18 (9, 1H), 7.88 (ad, 1H), 7.00 (9, 1H), 6.76 (a, 1H) , 6.70 (aa, 1), 6.30 (5, 2H), 3.80 (5, ЗН), 3.16 (ai, 2H), 3.02 (ad, 2H), 2.29 ( 5, ZN). GAM5 |MA-NI - 372.2

Example 70 ethyl 4-(2-(5-amino-8-methylbenzo (1, 7|Inaphthyridin-2-yl)ethyl)benzoate

MH,

M and She: - (Phi Phi Od o

Stage 1: Ethyl 4-((5-chloro-b6-cyanopyridin-3-yl)/ethynyl)benzoate

3,5-dichloropicolinonitrile solution (commercially available) (1.0 equiv), ethyl 4-ethynylbenzoate (commercially available) (1.0 equiv), trans-dichlorobis(triphenylphosphine)palladium(II) (10 molbb), iodide copper (I) (20 mol bb) and triethylamine (5.0 equiv.) in DMF (0.3 M) are stirred at 50 "C for 3 hours.

After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and 10 95 aqueous ammonium hydroxide. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Mod5O»4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMVIRG AN system (IZSO) using 0-20 96 ethyl acetate in hexane to give ethyl 4-((5-chloro-b6-cyanopyridin-3-yl)ethynyl)/benzoate in in the form of a white solid.

Stage 2: Ethyl 4-((5-amino-3-methylbenzo (1,7 |naphthyridin-2-yl)ethynyl)benzoate

A solution of ethyl 4-((5-chloro-6-cyanopyridin-3-yl)/ethynyl)benzoate (from the previous stage) (1.0 equiv.), tert-butyl 5-methyl-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate (from Example 5 / Step 2) (2.6 eq.), tetrakis(triphenylphosphine)palladium (10 molOo), and potassium carbonate (5, 3 equiv.) in a mixture of toluene/ethanol (2:11, 0.2 M) is stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture is diluted with 2 95 MeoN in OSM. The two phases are separated.

The combined organic phases are washed with saline, dried over anhydrous Mo5O", and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMBIRGABNO system (I5CO) using 0-40 90 ethyl acetate in toluene, which leads to the production of ethyl 4-((5-amino-Y-methylbenzoShP, 7|Inaphthyridin-2-yl)ethynyl)benzoate.

Stage 3: Ethyl 4-(2-(5-amino-8-methylbenzo|D(/1,7|naphthyridin-2-yl)ethyl)benzoate

A solution of ethyl 4-((5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)uethynyl)benzoate (from the previous step) (1.0 eq.) in THF/ethyl acetate (1:1, 0.05M) is flushed with nitrogen and palladium on charcoal (10 wt. 905) is added. The reaction vessel is evacuated, flushed with a stream of hydrogen, and stirred overnight at room temperature. The reaction mixture is filtered through celite, washed with 2 96 Meon in OSM , and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBGABNFO system (IZSO) using 0-5956 MeON in OSM, which gives ethyl 4-(2-(5-amino-8-methylbenzo|CD, 7Uinaphthyridine) -2-yl)ethyl)benzoate. "H

NMR (Acetone-av): b 8.80 (5, 1H), 8.69 (5, 1H), 8.25 (j, 1H), 7.90 (a, 2H), 7.40-7, 42 (t, ZN), 712 (a, 1H), 6.55 (g, 2H), 4.28 (ad, 2H), 3.2-3.3 (t, 4H), 2.44 (in , ZN), 1.31 (i, ZN). GAM5 (MANI - 386.2

Example 71 8-methyl-2-(4-methylphenethyl)benzo|ЦІ1, 7Inaphthyridin-5-amine

MN, O

M and Ua 0

Stage 1: 3-Chloro-5-(p-tolylethynyl)picolinonitrile

A solution of 3,5-dichloropicolinonitrile (commercially available) (1.0 equiv), 1-ethynyl-4-methylbenzene (commercially available) (1.0 equiv), trans-dichlorobis(triphenylphosphine)palladium(II) (10 mol ), copper(I) iodide (20 moles), and triethylamine (5.0 eq.) in DMF (0.3 M) were stirred at 502C for 3 hours.

After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and 1095 aqueous ammonium hydroxide. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous Md5O", and concentrated in vacuo. The crude material is purified by stirring in hot ether/hexane mixtures and filtered to give 3-chloro-5-(p-tolyethynyl)picolinonitrile.

Stage 2: 8-methyl-2-(p-tolylethynyl)benzo|(DI1,7|naphthyridin-5-amine

A solution of 3-chloro-5-(p-tolylethynyl)picolinonitrile (from the previous step) (1.0 equiv.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolane-2-ylphenylcarbamate (from Example 5 / Stage 2) (1.2 equiv.), tetrakis(triphenylphosphine)palladium (10 moles), and 2M aqueous sodium carbonate solution (4.0 equiv.) in a mixture of toluene/ ethanol (2:11,002 M) was stirred at 1002 C overnight. After cooling to room temperature, the reaction mixture was diluted with 295 MeoN in OSM. The two phases were separated and the aqueous layer was extracted with 2,956 MeoN in OSM twice. the combined organic phases are washed with saline, dried over anhydrous Mu95O54, and concentrated in vacuo.

The crude material is purified by flash chromatography on a SOMVIRGAZNF system (IZSO) using 0-40 96 ethyl acetate in toluene, which gives 8-methyl-2-(p-tolylethynyl/benzo DI, 7|naphthyridine-5-amine).

Stage 3: 8-methyl-2-(4-methylphenethyl)benzo| DI, 7|naphthyridine-5-amine

A solution of 8-methyl-2-(p-tolylethynyl)ubenzo DP, 7|Inaphthyridin-5-amine (from the previous stage) (1.0 equiv.) in a mixture of EYN/ethyl acetate (1:1, 0.05M) is irrigated with nitrogen and add palladium on charcoal (10 wt. 95). Air is pumped out of the reaction vessel, irrigated with a stream of hydrogen, and stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with 2 95 Meon in OSM, and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVINGA5NOE system (IZSO), using 0-5 96 MeoN in OSM, which leads to the production of 8-methyl-2-(4-methylphenethyl)benzo DP, 7|Inaphthyridin-5-amine. "H NMR (Acetone-dv): b 8.74 (5, 1Н), 8.68 (5, 1Н), 8.24 (9, 1Н), 7.41 (5,1Н), 7.13- 7.15 (t, ZN), 7.06 (a, 2H), 6.6 (rg, 2H), 3.19 (I, 2H), 3.06 (i, 2H), 2.44 (5 ,

ZN), 2.25 (5, ZN). And AM5 | MANI - 328.1

Example 72 2-(4-(2-(5-amino-8-methylbenzo| 1, 7| naphthyridin-2-yl) ethyl) phenyl) propan-2-ol much

M | My dream

SA (A dream

3.0 M is added to a solution of ethyl 4-(2-(5-amino-8α-methylbenzo DP, 7|Inaphthyridin-2-yl)ethyl)benzoate (from Example 70) (1.0 equiv.) in OCM at 02С methyl magnesium iodide (1O0 eq.) in ether and warmed to room temperature overnight. The reaction mixture is cooled to 02C and the reaction is quenched with 1M

NSI of aqueous solution and ether. After stirring for 15 minutes, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The two phases are separated, and the aqueous layer is extracted with ether. The combined organic phases are washed with saline, dried over anhydrous Md5O5, and concentrated in vacuo. The raw material is purified by means of OF-HPLC,

using a gradient of 10-50 90 MesmMm in water, followed by extraction in OSM, resulting in 2-(4-(2-(5-amino-d-methyl-benzoDY,7|naphthyridin-2-yl)ethyl)/ phenyl)propan-2-ol. "H NMR (Acetone-ab): b 8.73 (t, 2H), 8.22 (j, 1H), 7.40-7.44 (t, 3H), 7.20 (a, 2H), 7.12 (a, 1H), 6.5 (Bg, 2H), 3.94 (5, 1H), 3.21 (I, 2H), 3.08 (I, 2H), 2.44 (5 , ZN), 1.47 (5, 6H). And AM5 IMA-NI - 372.2

Example 73 (4-(2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)ethyluphenyl)methanol

MN

M | and: p

SA SA on

To a solution of ethyl 4-(2-(5-amino-1-methylbenzo(SHI, 7|naphthyridin-2-yl)oethyl)benzoate (Example 70) (1.0 equiv.) in THF (0.1 M) at 02C, 1.0 M lithium triethylborohydride in THF (10 equiv) is added and warmed to room temperature over 2 hours. 1 M aqueous HCl solution is added slowly to quench the reaction, and the mixture is heated to irrigation over 30 minutes. The reaction mixture is neutralized with saturated of aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ethyl acetate (EA). The combined organic phases were washed with brine, dried over anhydrous M95O54, and concentrated in vacuo. The crude material was purified by HPLC using a gradient 10-5095 MesmM in water, followed by extraction in OSM, which leads to obtaining (4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)/ethylphenyl)umethanol. " H NMR (Acetone-dv): b 8.77 (5, 1H), 8.69 (5, 1H), 8.26 (a, 1H), 7.40 (5, 1H), 7.21-7 .28 (t, 4H), 7.13 (y, 1H), 6.5 (bg, 2H), 4.56 (v, 2H) , 4.1 (ry, 1), 3.10-3.23 (t, AN), 2.44 (v, ZN). And AM5

IMAANI - 344.2

Example 74 ethyl 4-(2-(5-amino-8-methylbenzo CY, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate

MH,

M y: -d

I what (6;

Stage 1: Ethyl 4-bromo-33-methylbenzoate

To a solution of 4-bromo-3-methylbenzoic acid (commercially available) (1.0 eq.) in EUN (0.3 M) was added thionyl chloride (1.5 eq.) and heated to irrigation for 2 hours. The solvent is concentrated in vacuo, and the residue is diluted with ether and neutralized with a saturated aqueous solution of sodium bicarbonate. The two phases are separated, and the aqueous layer is extracted with ether. The combined organic phases are washed with brine, dried over anhydrous Md5O", and concentrated in vacuo to give ethyl 4-bromo-3-methylbenzoate.

Stage 2: Ethyl 3-methyl-4-(triethylsilyl)ethynyl)benzoate

A solution of ethyl 4-bromo-3-methylbenzoate (from the previous stage) (1.0 equiv.), triethyl(ethynyl)silane (1.1 equiv.), trans-dichlorobis(triphenylphosphine)palladium (I) (10 moles), copper(I) iodide (20 molObo) and triethylamine (5.0 equiv) in DMF (0.3 M) were stirred at 602C overnight. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and 10 95 aqueous ammonium hydroxide. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate.

The combined organic phases are washed with saline, dried over anhydrous Mo5O", and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVIRGSABNOE system (I5CO), using 0-590 ethyl acetate in hexane, which gives ethyl 3-methyl-4-(triethylsilyl)ethynyl)benzoate as a yellow oil.

Stage 3: Ethyl 4-ethynyl-3-methylbenzoate

1.0 M TVAE in THF (1. 2 eq.). After stirring for 10 minutes at 02C, the reaction is quenched with a saturated aqueous solution of sodium bicarbonate. The two phases are separated, and the aqueous layer is extracted with ether. The combined organic phases are washed with saline, dried over anhydrous M95O54, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGA5NO system (IZSO) using 0-5 95% ethyl acetate in hexane to give ethyl 4-ethynyl-3-methylbenzoate as a white solid.

Step 4: Ethyl 4-((5-chloro-b6-cyanopyridin-3-yl)/ethynyl)-3-methylbenzoate

A solution of 3,5-dichloropicolinonitrile (1.0 eq.), ethyl 4-ethynyl-3-methylbenzoate (from the previous step) (1.0 eq.), trans-dichlorobis(triphenylphosphine)palladium (I) (10 mol") , copper(I) iodide (20 moles), and triethylamine (5.0 equiv.) in DMF (0.3 M) were stirred at 502C for 3 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and 10 95 aqueous ammonium hydroxide. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate.

The combined organic phases are washed with saline, dried over anhydrous Mo5O", and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMBIRGSABNO system (I5CO) using 0-10 90 ethyl acetate in hexane, which gives ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate as a white solid.

Stage 5: Ethyl 4-((5-amino-3-methylbenzo (1,7 |Inaphthyridin-2-yl)ethynyl)-3-methylbenzoate

A solution of ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate (from the previous step) (1.0 eq.), tert-butyl 5-methyl-2-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane-2-ylphenylcarbamate (from Example / Step 2) (1.1 eq.), tetrakis(triphenylphosphine)palladium (8 mol), and potassium carbonate (3.0 eq.) in a mixture of toluene/ethanol (9:11, 002 M) is stirred at 1002C overnight. After cooling to room temperature, the reaction mixture is diluted with 295 MeoN in OSM. The two phases are separated. The combined organic phases are washed with brine , dried over anhydrous Mda5oOx, and concentrated in vacuo.The crude material was purified by flash chromatography on

SOMBIRGABNO system (I5CO) using 0-40 906 ethyl acetate in toluene, which leads to the production of ethyl 4-((5-amino-3-methylbenzoShrI, 7|Inaphthyridin-2-yl)ethynyl)-3-methylbenzoate.

Stage 6: Ethyl 4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyl)-3-methyl-benzoate

A solution of ethyl 4-(5-amino-8-methylbenzo(/1,7-inaphthyridin-2-yl)ethynyl)-3-methylbenzoate (from the previous step) (1.0 eq.) in a mixture of THF/ethyl acetate (1:1, 0.05M) is irrigated with nitrogen and 10 9o of palladium on charcoal (10 wt. 95) is added. Air is pumped out of the reaction vessel, irrigated with a stream of hydrogen, and stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with 2 96 MeoN in OSM, and concentrated in vacuo. The crude material is purified by flash chromatography on the SOMBIRGABNO system (IZSO) using 30-100,956 EA in hexane, which gives ethyl 4-(2-(5-amino-8-methylbenzo|/1,7|naphthyridine-2 -yl)ethyl)-3-methyl-benzoate. "H NMR (Acetone-dv): b 8.79 (5, 1H), 8.71 (5, 1H), 8.24 (y, 1H), 7.80 (5, 1H), 7.73 ( y, 1Hn), 7.40 (5, 1H), 7.91 (a, 1), 7.12 (0, 1), 6.5 (bg, 2H), 4.29 (d, 2H), 3.19-3.22 (t, 4H), 2.44 (5, ZN), 2.39 (in,

ZN), 1.31 (her, ZN). GAM5 (MANI - 400.2

Example 75 4-(2-(5-amino-8-methylbenzo DP, 7-Naphthyridin-2-yl)ethyl)-3-methylbenzoic acid

MH,

M | She: -d

And SA he about

To a solution of ethyl 4-(2-(5-amino-8α-methylbenzo DCP, 7Inaphthyridin-2-yl)ethyl)-3-methylbenzoate (with

of Example 74) (1.0 equiv.) in EUN, 1 M aqueous sodium hydroxide (1.5 equiv.) is added and heated to 8020 for 5 hours. The reaction mixture is neutralized by adding a 1M aqueous solution of HCl (1.5 equiv.) and concentrated in vacuo. The crude material is purified by HPLC using a gradient of 10-50 96 Mesm in water followed by concentration in vacuo to give

TEA salt. "H NMR (DMSO-dv) TRA salt: b 7.94-7.96 (t, 2H), 7.55 (9, 1H), 7.00 (5, 1H), 6.91 (a, 1H ), 6.62-6.66 (t, 2H), 6.39 (y, 1H), 2.36-2.5 (t, 4H), 1.73 (5, ЗН), 1.54 ( 5, ZN). And AM5 (MANI - 372.2

Example 76 (4-(2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)methanol much

M MU

-d-

I SA on

To a solution of ethyl 4-(2-(5-amino-8α-methylbenzo DCP, 7Inaphthyridin-2-yl)ethyl)-3-methylbenzoate (with

Example 74) (1.0 equiv.) in THF (0.1M) at -782С add 1.0 M SIVAG-N in toluene (10 equiv.) and heat to room temperature for 2 hours. A 1.5 M aqueous solution of ferrous salt is added slowly to quench the reaction accompanying the addition of EA, and this mixture is stirred for 45 minutes. The two phases are separated and the aqueous layer is extracted twice with EA. The combined organic phases are washed with saline, dried over anhydrous M95O54, and concentrated in vacuo.

The crude material is purified by PF-HPLC using a gradient of 10-50 96 Meskm in water, followed by extraction in OSM, which gives /(4-(2-(5-amino-8- methylbenzo DY, 7|naphthyridine- 2-yl)ethyl)-3-methylphenyl)methanol. "H NMR (Acetone-dv): b 8.77 (5, 1H), 8.71 (5, 1H), 8.25 (9, 1H), 7.41 (5, 1H), 7.10- 7.15 (t, AN), 6.5 (BI, 2H), 4.54 (5, 2H), 4.05 (horn, 1H), 3.08-3.18 (t, 4H), 2 .44 (5, ZN), 2.31 (5, ZN). And AM5 (MANI - 358.2

Example 77 8-methyl-2-(2,4,6-trimethylphenethyl)benzo|C1,7Inaphthyridin-5-amine

MH,

M | and: what

Stage 1: 3-Chloro-5-(mesitylethynyl)picolinonitrile

A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 2-ethynyl-1,3,5-trimethylbenzene (commercially available) (1.0 eq.), trans-dichlorobis(triphenylphosphine)palladium (I) (10 mol », copper (I) iodide (20 ml), and triethylamine (5.0 eq.) in DMF (0.3 M) were stirred at 502C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and 95% aqueous ammonium hydroxide. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M95O5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO) using 0-10 90 ethyl acetate in hexane, which gives 3-chloro-5-(mesitylethynyl)picolinonitrile as a white solid.

Stage 2: 2-(mesitylethynyl)-8-methylbenzo|D(1,7|naphthyridin-5-amine

A solution of 3-chloro-5-(mesitythylethynyl)picolinonitrile (from the previous step) (1.0 equiv.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolane-2-ylphenylcarbamate (from Example 5 / Stage 2) (1.1 eq.), tetrakis(triphenylphosphine)palladium (8 mol bb), and 2M aqueous sodium carbonate solution (3.0 eq.) in a mixture of toluene/ethanol ( 4:11.002 M) is stirred at 1002C overnight. After cooling to room temperature, the reaction mixture is diluted with 295 MeON in OSM. The two phases are separated. The combined organic phases are washed with brine, dried over anhydrous Ma5Z0O", and concentrated in vacuo The crude material is purified by flash chromatography on

SOMBIRGABNO system (I5CO), using 0-40 90 ethyl acetate in toluene, which leads to 2-(mesitylethynyl)-8-methyl-benzo CI, 7|Inaphthyridin-5-amine.

Stage 3: 8-methyl-2-(2,4,6-trimethylphenethyl)benzo DY, 7|Inaphthyridin-5-amine

A solution of 2-(mesitylethynyl)-8-methylbenzo| 1, 7UInaphthyridine-5-amine (from the previous stage) (1.0 equiv.) in EUN (0.05M) is flushed with nitrogen and palladium on charcoal (10 wt. 95) is added. Air is pumped out of the reaction vessel, irrigated with a stream of hydrogen, and stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with 2 95 MeOOnH in OSM, and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO) using 0-50 90 ethyl acetate in hexane, which leads to 8-methyl-2-(2,4,6-trimethylphenethyl)benzoi|C(1,7|Inaphthyridin-5-amine. "H NMR (Acetone-dv): b 8.73-8.74 (t, 2H), 8.25 (0, 1H), 7.42 (5, 1H), 7.14 (a, 1H), 6, 83 (5, 2H), 6.55 (ri, 2H), 3.07 (t, 4H), 2.47 (5,

ZN), 2.29 (in, 6H), 2.22 (z, ZN). And AM5 IM-ANI - 356.2

Example 78 2-(4-(2-(5-amino-8-methylbenzo| 1, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol much

M | M -d-

And SA is a dream

To a solution of ethyl 4-(2-(5-amino-8α-methylbenzo DCP, 7Inaphthyridin-2-yl)ethyl)-3-methylbenzoate (with

of Example 74) (1.0 equiv.) in OCM at 09C is added 3.0 M methyl magnesium iodide (1 Oeeeq.) in ether and heated to room temperature overnight. The reaction mixture is cooled to 02C and the reaction is quenched with water. After stirring for 15 minutes, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and EA is added. The two phases are separated and the aqueous layer is extracted three times with EA. The combined organic phases are washed with saline, dried over anhydrous M95O54, and concentrated in vacuo. The raw material is purified by flash chromatography on a SOMVIRGA5NO) system (IZSO), using 0-5 95 MeOnN in

OSM, leading to 2-(4-(2-(5-amino-8-methylbenzo|/1,7|naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol. "H NMR (Acetone-dv): b 8.72-8.75 (t, 2H), 8.23 (0, 1H), 7.41 (5, 1H), 7.32 (5, 1H), 7.25 (a, 1H), 7.12-7.14 (t, 2H), 6.6 (Bi, 2H), 3.91 (5, 1H), 3.07-3.18 (t, 4H), 2.44 (5, ZN), 2.31 (5, ZN), 1.48 (5, 6H). And AM5 |MA-NNI - 386.2

Example 79 8-methyl-2-(4-propoxyphenethyl)benzo CI, 7|Inaphthyridin-5-amine

MH,

M | Ve: 0 07

Stage 1: 3-chloro-5-((4-propoxyphenyl)ethynyl)picolinonitrile

A solution of 3,5-dichloropicolinonitrile (1.0 equiv), 1-ethynyl-4-propoxybenzene (commercially available) (1.0 equiv), trans-dichlorobis(triphenylphosphine)palladium(I) (10 mol”), iodide copper (I) (20 moles) and triethylamine (5.0 equiv.) in DMF (0.3 M) are stirred at 502C for 3 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and 10 95 aqueous ammonium hydroxide. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate.

The combined organic phases are washed with saline, dried over anhydrous Mo5O", and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO) using 0-10 90 ethyl acetate in hexane, which gives 3-chloro-5-((4-propoxyphenyl)ethynyl)picolinonitrile as a white solid.

Step 2: 3-chloro-5-(4-propoxyphenethyl)picolinonitrile

A solution of 3-chloro-5-((4-propoxyphenyl)ethynyl)picolinonitrile (from the previous step) (1.0 equiv.) in EtOH (0.05M) is flushed with nitrogen and platinum oxide (MI) (0.5 equiv.) is added. ). Air is pumped out of the reaction vessel, irrigated with a stream of hydrogen, and stirred for 5 hours at room temperature.

The reaction mixture was filtered through celite, washed with 295 MeON in OSM, and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO), using 0-15 9o ethyl acetate in hexane, which leads to the receipt of 3-chloro-5-(4-propoxyphenethyl)picolinonitrile.

Stage 3: 8-methyl-2-(4-propoxyphenethyl)benzo CHY, 7|naphthyridin-5-amine

A solution of 3-chloro-5-(4-propoxyphenethyl)picolinonitrile (from the previous step) (1.0 equiv.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane-2-ylphenylcarbamate (from Example 5 / Step 2) (1.1 eq.), tetrakis(triphenylphosphine)palladium (8 mol bb), and a 2M aqueous solution of sodium carbonate (3.0 eq.) in toluene (0 .2 M) was stirred at 1002 overnight. After cooling to room temperature, the reaction mixture was diluted with 295 MeOH in OSM. The two phases were separated. The combined organic phases were washed with brine, dried over anhydrous Md5O", and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMVIRGA5BNF system (IZSO) using 0-40 9o ethyl acetate in toluene, which leads to 8-methyl-2-(4-propoxyphenethyl)benzoi|C(1,7|Inaphthyridin-5- amine. "H NMR (Acetone-dv): b 8.74 (5, 1H), 8.67 (5, 1H), 8.24 (9, 1H), 7.41 (5, 1H), 7, 15-7.17 (t, ЗН), 6.81 (а, 2Н), 6.5 (би, 2Н), 3.687 (Й, 2Н), 3.18 (И, 2Н), 3.04 (и , 2H), 2.44 (5, ЗН), 1.73 (t, 2H), 0.99 (i, ЗН). And AM5 IMA-NI - 372.2

Example 80

(E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|C1, 7UInaphthyridin-8-yl)acrylate mn,

M | Mach che o t 6; (E)-Ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzoic acid, 7-naphthyridin-8-yl)isoacrylate is obtained from 5-amino-2-(4-methoxy-2 -methylphenethyl)benzo|D(1,7N-naphthyridine-8-carbaldehyde (from Example 69) and ethyl 2-(diethoxyphosphoryl)acetate (commercially available) following the procedures described for

Example 65 / Stage 3. And KM5 |MNI - 442.2

Example 81 (E)-3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|DP, 7|Inaphtyridin-8-yl)acrylic acid

Mn, kasa ve her no 6; (E)-3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo DP, 7|Inaphthyridin-8-yl)acrylic acid is obtained from (E)-ethyl 3-(5-amino-2 -(4-methoxy-2-methylphenethyl)-benzoyl,7|naphthyridin-8-yl)acrylate (from Example 80), following the procedures described for Example 68. "H NMR TRA salt (DMSO-dv): b 12, 66 (5, 1H), 9.09 (5, 1H), 8.68 (5, 1H), 8.66 (a, 1H), 7.95 (a, 1H), 7.91 (c, 1H ), 7.75 (9, 1H), 7.10 (a, 1H), 6.77-6.71 (t, 2H), 6.68 (ai, 1H), 3.70 (5, ЗН) , 3.16 (i, 2H), 3.00 (i, 2H), 2.30 (z, ЗN). I AM5 I(MA--NI - 414 2

Example 82 ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo DP, 7|Inaphthyridin-8-yl)upropanoate

Mn,

M | With another 07 t 6;

Ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo DY, 7|naphthyridin-8-yl)upropanoate is obtained from (E)-ethyl 3-(5-amino-2-(4- methoxy-2-methylphenethyl)benzo DI,7|Inaphthyridin-8-yl)acrylate (from Example 80), following the procedures described for Example 44 / Step 5. "H NMR (SOCI"): b 8.63 (a, 1H), 8.37 (a, 1H), 8.13 (9, 1H), 7.56 (9, 1H), 7.24 (da, 1n), 7.02 (a, tn), 6, 75 (a, 1), 6.69 (aa, 1), 6.15 (rg 5, 2H), 4.17 (a, 2H), 3.79 (5, ЗН), 3.12 (ad, 4H), 2.99 (aa, 2H), 2.75 (I, 2H), 2.29 (5, ЗН), 1.27 (I, 2Н), 0.99 (i, ЗН).

IGAM5IMANI - 444 2

Example 83 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo CHY, 7|naphthyridin-8-yl)upropanoic acid mn,

M 2 le o7 no 6; 3-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo H(/1,7uInaphthyridin-8-yl)upropanoic acid is obtained from ethyl 3-(5-amino-2-(4-methoxy-2 -methylphenethyl)-benzo(1,7|inaphthyridin-8-yl)upropanoate (from Example 82), following the procedures described for Example 68. "H NMR (DMSO-α): b 12.18 (5, 1H), 8.84 (y, 1H), 8.70 (9, 1H), 8.36 (a, 1), 7.39 (a, 1H), 7.20 (ad, 1H), 7.09 (t , 2H), 6.74 (a, 1H), 6.68 (aa, 1H), 3.70 (5, ЗН), 3.09 (ai, 2H), 2.96 (ad, 4H), 2 .63 (i, 2H), 2.27 (5, ZN). AND AM5 IMA--NI - 416.2

Example 84 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo-CH,7N-naphthyridin-8-yl)upropan-1-ol

Mn,

M. p

Ot o7 one 3-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo|DI, 7|Inaphthyridin-8-ylpropane-i-sl is obtained from ethyl 3-(5-amino-2-(4 -methoxy-2-methylphenethyl)benzo N/1,7|inaphthyridine-8-ylpropanoate (from Example 82), following the procedures described for Example 42 / Step 3. "H NMR (SOCI"): b 8.54 (a , 1H), 8.30 (9, 1Hn), 8.05 (y, 1H), 7.48 (9, 1H), 7.15 (ai, 1H), 6.93 (a, 1H), 6 .66 (a, 1H), 6.61 (aa, 1H), 5.98 (re 5, 2H), 3.71 (v, ЗН), 3.66 (i, 2H), 3.03 (aa , 2H), 2.91 (aa, 2H), 2.81 (i, 2H), 2.20 (5, ЗН), 1.98-1.90 (t, 2H). I VM5

IMANI - 402.2

Example 85 (5-aminobenzo(DI, 7|naphthyridin-8-yl)methanol

Mn,

M | Wow -

I5(9)

Stage 1: 2-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)/phenylboronic acid

A solution of 2-amino-4-(methoxycarbonyl)/phenylboronic acid hydrochloride (commercially available) (1.0 equiv.), triethylamine (3.0 equiv.), di-tert-butyl dicarbonate (1.1 equiv.), and LOBSTER (0.1 equiv.) in SNZSM (0.3 M) are stirred at 402C overnight. After cooling to room temperature, the reaction mixture is concentrated in vacuo to give a crude residue. The crude material was purified by flash chromatography on a SOMBIRGABNO system (IZSO) using 0-30906 Meon/losm to afford 2-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)-phenylboronic acid as a brown solid.

Stage 2: methyl 5-aminobenzo|C1, 7UInaphthyridine-8-carboxylate

A solution of 2-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)/phenylboronic acid (from the previous step) (1.0 equiv) and 3-bromopicolinonitrile (1.0 equiv), tetrakis(triphenylphosphine)palladium (5 molbob), and a 2M aqueous solution of sodium carbonate (2.0 eq.) in a mixture of toluene/ethanol (2:1, 0.03 M) is stirred at 10020 overnight. After cooling to room temperature, the reaction mixture is filtered to collect the precipitate. The precipitate is washed with EtOAc, which leads to the production of methyl 5-aminobenzo| 11, 7UInaphthyridine-8-carboxylate in the form of a pale brown solid.

Stage 3: (5-aminobenzo DY, 7|Inaphthyridin-8-yl)umethanol

Add methyl 5-aminobenzo to the solution DI, 7|naphthyridine-8-carboxylate (from the previous stage) (1.0 equiv.) in

EUN (0.03M) is added to Mavnae (10 equiv.) at 25 °C. This solution is heated to 80 °C for 5 hours.

After cooling to room temperature, the reaction mixture is concentrated in vacuo. The residue is partitioned between saturated NaHCO3 and EtOAc. The layers are separated and the aqueous layer is extracted twice with EtOAc. The combined organic layer is washed with saline solution, dried over

Ma95O: and concentrated in vacuo to give a crude residue. The raw material is purified by flash chromatography on the SOMBIRGABNOYA system (I5SO), using 0-10 95

Meon/OSmMm, leading to (5-aminobenzo|D/1,7|naphthyridin-8-ylmethanol) in the form of an off-white solid: "H NMR (methanol-dia): b 8.82 (ai, 1H) , 8.77 (da, 1H), 7.26 (y, 1H), 7.70 (aa, 1h), 7.50 (a, 1H), 7.27 (aa, 1H), 4.66 ( 5, 2H). AND AM5 | MA-NI - 2261.

Example 86

B-aminobenzo CY, 7Inaphthyridin-8-ol

Mn,

M and y: -d- no

To a solution of 8-methoxybenzo CHY, 7|naphthyridine-5-amine (from Example 10) (1.0 equiv.) in OSM (0.04 M) is added VV"gz (2.5 equiv.) dropwise in M2 at -202 C. The reaction mixture was allowed to warm to room temperature over 30 minutes.The reaction mixture was then stirred overnight.

The reaction is quenched with saturated MnSO 2 and extracted with EtOAc. The combined organic layer was washed with brine, dried over Mo95O4 and concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on

SOMVINGA5NOE system (IZSO), using 0-20 90 MEON/OSM, which leads to obtaining 5-aminobenzo| 411, 7UInaphthyridin-8-ol in the form of a yellow solid: "H NMR (acetone-dv): b 8.90 (aa, 1H), 8.83 (ad, 1n), 8.32 (a, 1), 7.83 (ad, 1H), 7.11 (Bri 5, 2H), 7.10 (9, 1H), 6.96 (ad, 1H), 5.86 (Brg 5, 1H).

GAM5 MANI - 212.1.

Example 87

B-aminobenzo CY, 7-Naphthyridine-8-carbaldehyde

Mn,

M M

- ns

A solution of (5-aminobenzo|DI1,7U-naphthyridine-8-ylmethanol (from Example 85) (1.0 equiv.) and activated

Mpo" (20 equiv.) in OSM (0.1 M) is stirred at room temperature overnight. The reaction mixture is diluted with the help of USM. MpO»2 is filtered, and the filtrate is concentrated in a vacuum to obtain a crude residue. The crude material is purified by flash chromatography on

to the SOMVINGA5NOE system (IZSO) using 0-10 90 MEON/OSM, which leads to the production of 5-aminobenzo DY, Uinaftyridine-8-carbaldehyde as a yellow solid: "H NMR (acetone-db): b 10.19 (5 , 1H), 9.14 (da, 1H), 9.01 (aa, 1n), 8.63 (a, 1H), 8.14 (a, 1Hn), 7.93 (ai, 1), 7 .81 (ad, 1H), 6.96 (Bbg 5, 2H). GAM5 (MANI - 224.1

Example 88 1-(5-aminobenzo|(D(I1,7|naphthyridin-8-yl)ethanol

MH,

M | "and - he

To a solution of 5-aminobenzo(Щ/1, 7U-naphthyridine-8-carbaldehyde (from Example 87) (1.0 equiv.) in THF (0.02 M) is added Meiy (2.5 equiv.) at -78 "C. Reaction the mixture is allowed to warm to room temperature overnight.The reaction is quenched with sat.

The combined organic layer was washed with brine, dried over MdbOx and concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMVIRGA5NO system (IZSO) using 0-5 96 MEOH/OSM, which leads to 1-(5-aminobenzo(Schy, 7U|Inaphthyridin-8-yl)oethanol as a yellow solid : "H NMR (methanol-ag): 6 8.94 (aa, 1Hn), 8.88 (aa, 1n), 8.38 (a, 1), 7.81 (da, 1H), 7.62 (a, 1), 7.41 (ad, 1n), 4.97 (ad, 1H), 1.53 (a, ZN). And AM5 (MANI - 240.1.

Example 89 1-(5-aminobenzo|(D(I1,7|naphthyridin-8-yl)ethanone

Mn,

M | Ua r o

A solution of 1-(5-aminobenzo|D/I1,7UInaphthyridin-8-yl)ethanol (from Example 88) (1.0 equiv.) and activated

Mpo" (20 equiv.) in OSM (0.1 M) is stirred at room temperature overnight. The reaction mixture is diluted with the help of USM. MpO:2 is filtered off, and the filtrate is concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on

to the SOMBINGA5NOE system (IZSO) using 0-5 96 MEON/OSM, which leads to the production of 1-(5-aminobenzo DY, Naphthyridin-8-yl)ethanone in the form of a yellow solid: "H NMR (acetone-av): b 9.11 (aa, tn), 8.99 (aa, 1nH), 8.56 (a, 1H), 8.20 (a, 1H), 7.94-7.88 (t, 2H), 6 .90 (rg in, 2H), 2.70 (5, ZN). And AM5

IMANNI - 238.1.

Example 90 8-isopropylbenzo H(1, 7|naphthyridine-5-amine

Mn,

M i y: rya

Stage 1: 2-(5-aminobenzo DY, 7|naphthyridin-8-yl)upropan-2-ol

To a solution of methyl 5-aminobenzo(/1,7|Inaphthyridine-8-carboxylate (from Example 85 / Stage 2) (1.0 equiv.) in THF (0.02 M) is added MegGi (10 equiv.) at -78 " C. The reaction mixture was allowed to warm to room temperature overnight.The reaction was quenched with saturated MNeACI and extracted with

ETUOAss. The combined organic layer was washed with brine, dried over Md5O4 and concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMVIRGA5ZNO system (IZSO) using 0-10 96 MeOnH/OSM, which leads to 2-(5-aminobenzo|(DSHI1,7|naphthyridin-8-yl)/propan-2-ol in the form of yellow oil.

Stage 2: 8-(prop-1-en-2-ylubenzo(DI, 7|naphthyridine-5-amine

A solution of 2-(5-aminobenzo| (1, 7|naphthyridin-8-yl)/upropan-2-ol (from the previous step) (1.0 equiv.) and p-

T5OH (2 equiv.) in toluene (0.01 M) is stirred at 90 "C for 6 hours. The reaction is quenched with saturated

ManHsCO3 and extracted with EOAc. The combined organic layer was washed with brine, dried over M9505 and concentrated in vacuo to give a crude residue. The crude material is purified by means of flash chromatography on a SOMBIRGAS system (IZSO) using 0-5 90 meonlosm, which leads to the receipt of 8-(prop-1-en-2-yl/benzo|(ЦЙ1,7|naphthyridin-5-amine as a yellow solid.

Stage 3: 8-isopropylbenzo(I, 7|naphthyridine-5-amine

A mixture of 8-(prop-1-en-2-yl/benzoShP, 7|Inaphthyridin-5-amine (from the previous stage) (1.0 equiv.) and Ra/C (wet, 10 95 wt.) in EUN is stirred at NO from the flask overnight. The reaction mixture is diluted with SOSM. The Ra/C is filtered through celite and the filtrate is concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMBIRGAB system (I5CO) using 0-60905 EAbs /hexanes, which leads to the production of 8-isopropylbenzo|C(1,7|Inaphthyridin-5-amine in the form of a yellow solid: "H NMR (acetone-dv): b 8.98 (а4, 1Н), 8.88 (ad, 1H), 8.37 (a, 1Hn), 7.83 (da, 1), 7.49 (a, 1H), 7.27(d4, 1H), 6.66 (Bg 5, 2H ), 3.10-3.00 (t, 1H), 1.33 (9, 6H). And AM5 (MANI - 238.1.

Example 91 8-vinylbenzo| SHI, YInaphthyridine-5-amine

Mn,

M | and: -

J

To a solution of methyl-triphenyl-phosphonium iodide (6.0 equiv.) is added pViii (7.0 equiv.) at -78 70.

The reaction mixture is allowed to warm to 0 "C and stirred for 30 minutes (intense yellow-hot color). The reaction mixture is cooled again to -71787C, and 5-aminobenzo| (1, 7|naphthyridine-8-carbaldehyde (from Example 87) (1, 0 equiv) in THF was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated MNACI and extracted with EAs. The combined organic layer was washed with brine, dried over Mo95O4, and concentrated in vacuo with obtaining a crude residue.The crude material is purified by flash chromatography on

SOMVINGA5NE system (IZSO), using 0-50 96 E(Ac/hexanes, which leads to the production of 8-vinylbenzo DP, 7-Naphthyridin-5-amine in the form of a white solid: "H NMR (acetone-dv): "H NMR ( acetone-dv): b 9.00 (da, 1H), 8.90 (aa, 1H), 8.41 (a, 1Hn), 7.84 (da, 1H), 7.65 (a, 1H) , 7.52 (a4, 1H), 6.91 (da, 1H), 6.77 (g 5, 2H), 5.97 (aa, 1H), 5.34 (aa, 1n). MANY - 222.1.

Example 92 8-ethylbenzo DI, 7|naphthyridine-5-amine

MH,

M Me -

A mixture of 8-vinylbenzo|(D(Y1, U-naphthyridine-5-amine (1.0 equiv)) (from Example 91) and Ra/C (wet, 10 95 wt.) in EYN is stirred at H5 from a flask overnight. The reaction the mixture is diluted with

OSM Ra/C is filtered through celite, and the filtrate is concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on the SOMBIRGABZNO system (IBSO) using 0-60 95 EOAc/hexanes, which leads to the production of 8-ethylbenzo DP, 7-Naphthyridin-5-amine in the form of a white foam: "H NMR (acetone-dv) : b 8.984, 1H), 8.88 (da, 1H), 8.35 (a, 1Hn), 7.82 (aa, tn), 7.46 (a, 1H), 7.22 (ad, 1H ), 6.63 (corner 5, 2H), 2.78 (a, 2H), 1.30 (her, ZN). And AM5

IMANI - 2241.

Example 93 8-(Methoxymethyl)benzo PI, 7|Inaphthyridin-5-amine

Mn,

M y: -d-

Meow

Stage 1: tert-butyl 2-chloro-5-(methoxymethyl)phenylcarbamate

To a solution of 2-chloro-5-(methoxymethyl)aniline (commercially available) (1.0 equiv.) in THF (0.2 M) at 0" in an M2 atmosphere, TM Manmoz (2.5 equiv.) is added dropwise. The reaction the mixture is stirred for 15 minutes at 02 C, and a solution of di-tert-butyl dicarbonate in THF is added. The reaction mixture is warmed to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with 0.1 M aqueous HCl. The aqueous suspension is extracted twice by using

EUAs. The combined organic phases are washed with saline, dried over anhydrous Md5boOx, and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVINGA5NE system (IZSO), using 0-30 96 E(OAc/hexanes), which leads to obtaining tert-butyl 2-chloro-5-(methoxymethyl)phenylcarbamate in the form of a colorless oil.

Stage 2: tert-butyl 5-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate

Tert-butyl 2-chloro-5-(methoxymethyluphenylcarbamate (from the previous step) (1.0 equiv., 4,4,4245,5,5,5-octamethyl-2,2"-6i(1,3,2- dioxaborolane) (3.0 equiv.), Ragaraz (2.596), KhRNovz (10 95), and

COAc (3 eq.) is mixed in dioxane (0.2 M) in a Me atmosphere. The reaction mixture is heated to 1102C and stirred overnight. The obtained suspension is cooled to room temperature, diluted with ether, filtered through celite, and the filtrate is concentrated in a vacuum. The combined organic phases are washed with saline, dried over anhydrous M95O54, and concentrated in vacuo.

The crude material is purified by flash chromatography on a SOMVIRGAZNF system (IZSO) using 0-20 95 EIOAc/hexanes, which leads to the receipt of tert-butyl 5-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)uphenylcarbamate in the form of a white foam.

Stage 3: 8-(Methoxymethyl)benzo OR, 7|Naphthyridin-5-amine

A solution of tert-butyl 5-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from the previous step) (1.0 equiv.) and C -bromopicolinonitrile (1.0 equiv.) in toluene (0.44

M) is mixed with tetrakis(triphenyl-phosphine)palladium (5 molebobo) and 2M aqueous potassium carbonate solution (2.0 equiv.). The reaction mixture was heated to 100 °C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with 2,956 MeO in OSM and water. The two phases were separated and the aqueous layer was extracted twice with 295 MeO in OSM. The combined the organic phases are washed with brine, dried over anhydrous Md5O", and concentrated in vacuo. The crude material is purified by means of flash chromatography on a SOMVIRGA5BNF system (5CO) using 0-100 95 BEfOAc/hexanes, which leads to obtaining /(8- (methoxymethyl )benzo|C(1,7Inaphthyridin-5-amine in the form of a white solid substance: "H NMR (methanol-da): b 8.97 (ai, 1H), 8.91 (aa, 1H), 8.41 ( da, 1H), 7.83 (aa, 1n), 7.59 (a, 1H), 7.37 (ad, 1H), 4.62 (5, 2H), 3.45 (5, ЗН). And AM5 (MANI - 2401.

Example 94 (5-amino-2-phenethylbenzoxy, 7|Inaphthyridin-8-yl)methanol

Mn,

M | and: rya

F

Stage 1: methyl 5-amino-2-phenethylbenzo SHII, 7|Inaphthyridine-8-carboxylate

A solution of 2-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)-phenylboronic acid (from Example 85 / Step 1) (1.0 equiv; and 2-chloro-6-phenethylnicotinonitrile (obtained from (E)-3-chloro- 5-styrylpicolinonitrile (from Example 32 / Stage 1) following the procedure described in Example 114 / Stage 3) (1.0 eq.), tetrakis(triphenylphosphine)palladium (5 molybo), and 2M aqueous sodium carbonate solution (2 .0 equiv) in toluene/ethanol (2:1, 0.03 M) was stirred at 1002 overnight. After cooling to room temperature, the reaction mixture was diluted with EOAc and water. The two phases were separated and the aqueous layer was extracted twice with EAs. The combined organic phases are washed with brine, dried over anhydrous Mo2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIBABNFFOIA system (IZSO) using 0-60 90 EtOAc/hexanes, giving obtaining methyl 5-amino-2-phenethylbenzo|C1, 7UInaphthyridine-8-carboxylate in the form of a white solid.

Stage 2: (5-amino-2-phenethylbenzo|D(1,7|naphthyridin-8-ylmethanol

To a solution of methyl 5-amino-2-phenethylbenzo C(1,7|Inaphthyridine-8-carboxylate (from the previous stage) (1.0 equiv.) in THF (0.03M) add Zyreg-H (10 equiv.) at 0 "C. This solution is allowed to warm to room temperature over 30 minutes. The reaction is quenched with water until bubbling ceases. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with brine, dried over Md5O54, and concentrated in vacuo with obtaining a crude residue. The crude material is purified by means of flash chromatography on a SOMBIR AZNO system (IZSO) using 0-109o Meonlosm, which leads to obtaining (5-amino-2-phenethylbenzo|C1, 7UInaphthyridin-8-ylmethanol) in the form of an off-white of a solid substance: "H NMR (methanol-c): b 8.63 (ad, 1H), 8.56 (aa, 1H), 8.24 (a, 1H), 7.57 (a, 1H), 7 .35 (aa, 1H), 7.27-7.15 (t, 5H), 4.75 (v, 2H), 3.20 (her, 2H), 3.06 (her, 2H). And AM5 |MANI - 330.1.

Example 95

(5-amino-2-(4-methoxyphenethyl)benzo|DI, 7|Inaphthyridin-8-yl)methanol

MH,

M and "a -

Zh SA

Ome

Stage 1: methyl 5-amino-2-(4-methoxyphenethyl)benzo C(1,7|Inaphthyridine-8-carboxylate

A solution of 2-(tert-butoxycarbonylamino)-4-(methoxycarbonyl/phenylboronic acid (from Example 85 / Step 1) (1.0 eq.) and 2-chloro-6-(4-methoxyphenethyl)nicotinonitrile (obtained from reaction 3, 5-dichloropicolinonitrile with 1-ethynyl-4-methoxybenzene, following the procedure described in Example 44 /

Step C and recovery of the product following the procedure described in Example 114 / Step 3) (1.0 equiv.), tetrakis(triphenylphosphine)palladium (5 molebobo), and 2M aqueous sodium carbonate solution (2.0 equiv.) in mixture of toluene/ethanol (2:1, 0.03 M) is stirred at 1002C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water. The two phases are separated and the aqueous layer is extracted twice with EAs. The combined organic phases are washed with saline, dried over anhydrous M95O54, and concentrated in vacuo. The crude material is purified by flash chromatography on the SOMVIRGABNOYE system (IZSO), using 0-80 95

EtOAc/hexanes, resulting in methyl 5-amino-2-(4-methoxyphenethyl)benzo HCI, 7-Naphthyridine-8-carboxylate as a white solid.

Stage 2: (5-amino-2-(4-methoxyphenethyl)benzo C, 7|naphthyridin-8-yl)umethanol

Zyreg-H ( 10 eq.) at 0 "C. This solution is allowed to warm to room temperature over 30 minutes. The reaction is quenched with water until bubbling stops. The layers are separated and the aqueous layer is extracted with EAs. The combined organic layer is washed with brine, dried over Mo95O4 and concentrated in vacuo to give a crude residue.The crude material was purified by flash chromatography on

SOMVINGA5NOE system (IZSO), using 0-100 96 E(Ac/hexanes), which leads to the receipt of (5-amino-2-(4-methoxyphenethyl)-benzo|ЦІ1,7ІNaphthyridin-8-ylmethanol in the form of an off-white solid (31 95): "H NMR (acetone-av): b 8.79 (a, 1H), 8.70 (a, 1H), 8.35 (a, 1H), 7.61 (a, 1) , 7.33 (da, 1H), 7.13 (a, 2H), 6.83 (a, 2H), 6.62 (horn 5, 2H), 4.47 (5, 2H), 4.40 (ri 5, 1H), 3.75 (5, ZN), 3.22 (I, 2H), 3.06 (i, 2H). GAM5 MANI - 360.2.

Example 96 benzo SHII, 7-Naphthyridine-5,8-diamine

Mn,

M | y: t nom

Stage 1: tert-butyl 2-bromo-5-nitrophenylcarbamate

To a solution of 2-bromo-5-nitroaniline (commercially available) (1.0 equiv.) in THF (0.2M) at 0 C in a M2g atmosphere, 1M Manmo5 (2.5 equiv.) is added dropwise. The reaction mixture is stirred for 15 minutes at 0 °C, and a solution of di-tert-butyl dicarbonate in THF is added. The reaction mixture is heated to room temperature overnight. The solvent is evaporated, and the resulting residue is quenched with 0.1 M aqueous HCl. the suspension is extracted twice with

EUAs. The combined organic phases are washed with saline, dried over anhydrous Md5boOx, and concentrated in vacuo. The crude material is purified by flash chromatography on

SOMVINGA5NE system (IZSO), using 0-30 906 E(OAc/hexanes), which leads to the receipt of tert-butyl 2-bromo-5-nitrophenylcarbamate in the form of a colorless oil.

Stage 2: tert-butyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenyl-carbamate)

Tert-butyl. 2-Bromo-5-nitrophenylcarbamate (from previous stage) (1.0 equiv.), 44,44,5,5,5,5-octamethyl-2,2/-6i(1,3,2-dioxaborolane) ( 1.8 equiv.), dichloroI1,1'-bisidiphenylphosphino)ferrocene|palladium (II) (590), and sodium acetate (4.5 equiv.) are mixed in dioxane (0.2 M) under a Me atmosphere. The reaction mixture is heated to 100 "C and stirred overnight. The resulting suspension is cooled to room temperature, diluted with ether, filtered through Celite, and the filtrate is concentrated in vacuo.

The residue is purified by flash chromatography on a SOMBSA5BNOA system (IZSO) using 0-30 95 EtOAc/hexanes, which leads to tert-butyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolane-2-iluphenyl-carbamate in the form of a white foam.

Stage 3: β-NitrobenzoShP,7|Inaphthyridin-5-amine

A solution of tert-butyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)uphenylcarbamate (from the previous step) (1.0 eq.) and 3-bromopicolinonitrile (1.0 equiv.) in toluene (0.44 M) is mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2M aqueous potassium carbonate solution (2.0 equiv.).

The reaction mixture is heated to 100 "C and stirred overnight. After cooling to room temperature, the reaction mixture is filtered to collect the precipitate. This precipitate is washed with

EUAs, which leads to the production of 8-nitrobenzo CI, 7-Naphthyridin-5-amine as a yellow solid.

Stage 4: benzoII1,7|Inaphthyridine-5,8-diamine

A mixture of 8-nitrobenzo|DY1,7|naphthyridine-5-amine (from the previous stage) (1.0 eq.) and Ra/C (wet, 95 wt.) in ЕУН is stirred under Но from a cylinder during the night. The reaction mixture is diluted using OCM. The insoluble solid was filtered through celite, and the filtrate was concentrated in vacuo to give a crude residue. The crude material is washed with acetone, which gives benzo(/1,7|inaphthyridine-5,8-diamine in the form of an off-white solid substance:

NMR (methanol-di): b 8.73 (ai, 1Н), 8.71 (da, 1Н), 8.11 (а, 1Н), 7.69 (ай, 1нН), 6.86 (y , 1Hn), 6.82 (yes, 1H). HeMm5 (MANI - 211.1.

Example 97 8-(aminomethyl)benzo|D/1,7|naphthyridin-5-amine

MH,

M and Ua - d

Nm

Stage 1: 2-(tert-butoxycarbonylamino)-4-cyanophenylboronic acid

The title compound is prepared in accordance with the procedure described in Example 85 / Step 1, but using 2-amino-4-cyanophenylboronic acid hydrochloride (commercially available) as starting material. The crude material is purified by flash chromatography on a SOMBIR AZNF system (I5SO) using 0-30 96 Meonlosm, which gives 2-(tert-butoxycarbonylamino)-4-cyanophenylboronic acid as an off-white solid.

Stage 2: 5-aminobenzo DY 7|naphthyridine-8-carbonitrile

The title compound is prepared according to the procedure described in Example 96 / Step 3, but using 2-(tert-butoxycarbonylamino)-4-cyanophenylboronic acid (from the previous step) as starting material. The crude material is washed with a 1:1 mixture of E(OAc)/hexanes, which gives 5-aminobenzo(SHYP,7|Inaphthyridine-8-carbonitrile as a pale yellow solid.

Stage 4: benzoII1,7|Inaphthyridine-5,8-diamine

A mixture of 8-nitrobenzoic acid, 7-amino-naphthyridine-5-amine (from the previous stage) (1.0 equiv.) and Raney nickel (wet, 10 95 wt.) in a mixture of AlN/ammonium (2:1) is stirred under N balloon during the night. The reaction mixture is diluted using OCM. The insoluble solid was filtered through celite, and the filtrate was concentrated in vacuo to give a crude residue. The crude material is washed with 1095 Meon/OsCm and 7095 E(OAc/hexanes) to give benzo DP, 7U-naphthyridine-5,8-diamine as an off-white solid: "H NMR (methanol-da): b 8 .97 (da, 1n), 8.90 (ad, 1H), 8.41 (a, 1n), 7.83 (aa, 1nH), 7.57 (9, 1H), 7.39 (ad, 1H), 3.96 (in, 2). And AM5 |M--NI - 22941.

Example 98

Z-fluoro-8-methylbenzo OR, 7|naphthyridin-5-amine

MH,

M / We -

Stage 1: 3-Chloro-8-methylbenzo CHY, 7|Naphthyridin-5-amine

A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenyl-carbamate (with

of Example 5 / Stage 2) (1.0 equiv.) and 3-bromo-6b-chloropicolinonitrile (from Example 20 / Stage 2) (1.0 equiv.), tetrakis(triphenylphosphine)palladium (5 molybo), and A 2M aqueous solution of sodium carbonate (2.0 equiv.) in a mixture of toluene/ethanol (2:1, 0.03 M) is stirred at 1002C overnight. After cooling to room temperature, the reaction mixture is diluted with EOAc and water. The two phases are separated and the aqueous layer is extracted twice with EtOAc. The combined organic phases are washed with saline, dried over anhydrous M95O54, and concentrated in vacuo. The raw material is purified by flash chromatography on the SOMBIRGABNYA system (I5SO), using 0-40 95

EtOAc/hexanes, resulting in 3-chloro-8-methylbenzo(C1,7|naphthyridin-5-amine) as a pale yellow solid.

Stage 2: 3-fluoro-8-methylbenzo C1,7|Inaphthyridin-5-amine

A mixture of 3-chloro-8-methylbenzoic acid, 7-inaphthyridin-5-amine (from the previous step) (1.0 equiv.), potassium fluoride (4.0 equiv.), and 18-crown-β6 (0.4 equiv. ) in MMP (0.1 M) is heated in a microwave reactor at 210 C for 2 hours. After cooling to room temperature, the remainder of the reaction mixture is purified by means of flash chromatography on a SOMBIRGAZNO) system (IZSO) using 0-96 EOAc/hexanes, which leads to obtaining 3-fluoro-8-methylbenzo|DC/I1, 7|Inaphthyridine- 5-amine as a white solid. "H NMR (acetone-dv): b 9.20 (da, 1H), 8.32 (y, 1H), 7.58 (aa, 1Hn), 7.46 (a, 1H), 7.21 ( ad, 1H), 6.51 (Bg 5, 2H), 2.47 (z, ZN). And AM5 |(M-NI - 228.1.

Example 99 (5-amino-3-fluorobenzoic acid

Mk | I had a problem

Stage 1: tert-butyl 5-(tert-butyldimethylsilyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)/phenylcarbamate

The title compound is prepared in accordance with the procedure described in Example 93 / Stage 1 and 2, but using 5-(tert-butyldimethylsilyloxy)methyl)-2-chloroaniline (commercially available) as starting material. The crude material is purified by flash chromatography on a SOMBIE AZNF system (IZSO) using 0-20 95 EtOAc/hexanes, which gives tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)uphenyl-carbamate in the form of a white foam.

Stage 2: 8-(tert-butyldimethylsilyloxy)methyl)-3-chlorobenzo DI, YInaphthyridin-5-amine

The title compound was prepared in accordance with the procedure described in Example 98 / Step 1, but using tert-butyl 5-(tert-butyldimethylsilyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-iluphenylcarbamate (from the previous step) as starting material. The crude material is purified by flash chromatography on a SOMBIRGAZNO) system (IZSO) using 0-1595 EfOAc/hexanes to give 8-(tert-butyldimethylsilyloxy)methyl) -3- chlorobenzo SHI, 7|Inaphthyridin-5-amine in the form of a pale yellow solid.

Stage 3: (5-amino-3-chlorobenzo-CH, 7|naphthyridin-8-yl)umethanol

A solution of 8-(tert-butyldimethylsilyloxy)methyl)-3-chlorobenzo DP, 7|Inaphthyridin-5-amine (from the previous step) (1.0 eq.) and TVAE (1.1 eq.) in THF is stirred at room temperature during the night The reaction is quenched with saturated MansSoz. The two phases are separated and the aqueous layer is extracted twice with EBO. The combined organic phases are washed with saline, dried over anhydrous Md5O5, and concentrated in vacuo. The crude material was purified by flash chromatography on a SOMBIRGAB system (I5CO) using 0-595 MeOH to afford (5-amino-3-chlorobenzo[D/I1,7-Naphthyridin-8-yl)methanol as a white solid.

Stage 4: (5-amino-3-fluorobenzo DP, 7|Inaphthyridin-8-yl)umethanol

The title compound is prepared according to the procedure described in Example 98 / Step 2, but using (5-amino-3-chlorobenzo DP, 7|Inaphthyridin-8-yl)umethanol (from the previous step) as starting material. The crude material is purified by flash chromatography on a SOMBIR AZNF system (IZSO) using 0-40 95 EtOAc/hexanes, which gives (5-amino-3-fluorobenzoic acid, 7|Inaphthyridin-8-yl)methanol as a white solid matter. "H NMR (methanol- da): b 9.15 (da, 1n), 8.38 (a, 1H), 7.64 (a, 1H), 7.55 (aa, 1H), 7.41 ( aa, 1n), 4.77 (5, 2H). GAM5 (MANI - 2441.

Example 100

Z-chlorobenzo SHII, 7|Inaphthyridine-5,8-diamine

MH,

M | Think about us

Stage 1: C-chloro-8-nitrobenzo|DI1,7|naphthyridine-5-amine

The title compound was prepared according to the procedure described in Example 98 / Step 1, but using tert-butyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) uphenyl carbamate (commercially available) as starting material. The crude material is purified by flash chromatography on a SOMBIRGAB system (I5CO) using 0-4095 EAs/hexanes to afford 3-chloro-8-nitrobenzo(CI1,7|naphthyridine-5-amine) as a pale yellow solid .

Stage 2: Z-Chlorobenzo CI, 7|Inaphthyridine-5,8-diamine

A mixture of 8-nitrobenzox,7|naphthyridine-5-amine (from the previous step) (1.0 eq.) and Raney nickel (wet, 10 95 wt.) in EJN is stirred under pressure from a flask overnight. The reaction mixture is diluted with the help of USM. The insoluble solid was filtered through celite, and the filtrate was concentrated in vacuo to give a crude residue. The raw material is purified by flash chromatography on the SOMVIRGABNF system (I5SO), using 0-100 95

EtOAc/hexanes, resulting in 3-chlorobenzo| CI, 7|Inaphthyridine-5,8-diamine as a white solid. "H NMR (methanol-d4): b 8.75 (a, 1Hn), 8.08 (ai, 1H), 7.70 (a, 1Hn), 6.84-6.81 (t, 2H).

IGAM5 MANI - 245.1.

Example 101

Z-fluorobenzoic acid, 7-inaphthyridine-5,8-diamine

MH,

M | ME - nom

The title compound was prepared in accordance with the procedure described in Example 98/Stage 2, but using 3-chlorobenzo|X/1,7|Inaphthyridine-5,8-diamine (from Example 100) as starting material.

The crude material is purified by flash chromatography on a SOMVIRGAZNF system (IZ5SO) using 0-7 96 MeOnN/OSM, which leads to the production of 3-fluorobenzo|ЦІ1, 7|Inaphthyridine-5,8-diamine as a white solid. "H NMR (methanol-da): b 8.93 (da, 1H), 8.09 (a, 1H), 7.44 (aa, 1H), 6.86-6.83 (t, 2H). And VM5 (MANI - 229.1.

Example 102 8-isobutylbenzo|ЦІ1, YInaphthyridin-5-amine

MH,

M | "a - 8-Isobutylbenzol, 7|naphthyridine-5-amine is prepared from 5-aminobenzol, 7|naphthyridine-8-carbaldehyde (from Example 87) with isopropyl(triphenyl/uphosphonium bromide) following the procedures described for Example 91 (reaction Wittig) and Example 92 (reduction). "H NMR (acetone-av): b 8.98 (a9, 1H), 8.88 (aa, 1), 8.35 (9, 1H), 7.82 ( aa, 1H), 7.44 (9, 1H), 7.18 (aa, 1H), 6.73 (re 5, 2H), 2.63 (a, 2H), 2.04-1.94 ( t, 1H), 0.94 (0.6H). And AM5 (MANI - 252.1.

Example 103 (E)-8-(prop-1-enyl)/benzo|DI1,7|naphthyridin-5-amine

Mn,

(E)-8-(prop-1-enyl/ubenzo|(DI1,7|naphthyridine-5-amine) is obtained from 5-amino-benzo|ЦІ1,7UInaphthyridin-8-carbaldehyde (from Example 87) with ethyl(triphenyl)/phosphonium bromide following the procedures described for Example 91. "H NMR (acetone-sv): b 8.98(4a, 1H), 8.88 (da, 1H), 8.36 (a , 1n), 7.83 (ai, 1H), 7.54 (a, 1H), 7.43 (ad, 1H), 6.67 (bg5, 2H), 6.60-6.42 (t , 2H), 1.92 (aa, ZN). And AM5 (MANI - 236.1.

Example 104 8-propylbenzo CHIP, 7|Naphthyridin-5-amine

Mn,

M | and: - 8-Propylbenzo|(ЦІ1, 7UInaphthyridin-5-amine is obtained from (E)-8-(prop-1-enyl)-benzo DP, 7|Inaphthyridin-5-amine (from Example 103), following the procedures, described for Example 92. "H NMR (acetone-av): b 8.99 (ad, 1), 8.88 (ai, 1), 8.35 (a, 1H), 7.83 (ad, 1) , 7.45 (9, 1H), 7.21 (aa, 1H), 6.64 (horn 5, 2H), 2.74 (I, 2H), 1.74 (di, 2H), 0.98 (i, ZN). And AM5 (MANI - 238.1.

Example 105 8-(2-cyclopropylethyl)benzo TSI, 7-Naphthyridin-5-amine

Mn,

M. Z

- 8-(2-Cyclopropylethyl)benzo|(D(1,7|naphthyridin-5-amine) is obtained from 5-amino-benzo DP, 7U-naphthyridine-8-carbaldehyde (from Example 87) with (cyclopropylmethyl)-triphenylphosphonium bromide, following procedures described for Example 91 (Wittig reaction) and Example 92 (reduction). "H NMR (acetone-av): b 8.99(da, 1), 8.88 (ad, 1n), 8.35 (a , 1Hn), 7.83 (ai, 1), 7.47 (a, tn), 7.23 (ad, 1H), 6.64 (rg 5, 2H), 1.60 (9, 2H), 1.34-1.25 (t, 1H), 0.91-0.72 (t, 2H), 0.45-0.41 (t, 2H), 0.11-0.07 (t, 2H ).And AM5 |M-NI - 264.1.

Example 106 8-phenethylbenzo SH, 7|Naphthyridin-5-amine

MN.

M Mach

DI

8-PhenethylbenzoCI, 7|Naphthyridin-5-amine is prepared from 5-aminobenzoCI, 7|Naphthyridine-8-carbaldehyde (from Example 87) with benzyltriphenylphosphonium bromide following the procedures described for Example 91 (Wittig reaction) and Example 92 (reduction ). "H NMR (acetone-sv): b 8.99 (ai, 1), 8.88 (aa, 1), 8.35 (a, 1H), 7.83 (aa, 1H), 7.49 ( a, 1n), 7.29-7.15 (aa, 6H), 6.70 (Be 5, 2H), 3.10-3.00 (t, 4H).

GAM5IMANI - 300.1.

Example 107 (5-amino-2-(4-bromophenethyl)benzo|C1,7UInaphthyridin-8-ylmethanol

Mn,

M | She: to vo. I am FI

Bg (5-Amino-2-(4-bromophenethyl)benzo HCI, 7|Inaphthyridin-8-yl)umethanol is obtained from (5-amino-2-(4-methoxyphenethyl)benzo HCI, 7Inaphthyridin-8-yl)umethanol ( from Example 95), following the procedures described for Example 86. "H NMR (acetone-av): b 8.81 (a, 1H), 8.72 (j, 1H), 8.40 (4, 1H), 7.68 (a, 1H), 7.39 (aa, 1n), 7.08 (9, 2H), 6.74 (a, 2H), 6.66 (g 5, 2H), 4.49 ( 5, 2H), 3.21 (I, 2H), 3.03 (her, 2H). I AM5 |M.ANI - 408.1.

Example 108 (5-amino-2-(4-methoxy-2-methylphenethyl)benzo CH, 7|naphthyridin-8-yl)methanol

Mn,

M M

- about F

OMe (5-Amino-2-(4-methoxy-2-methylphenethyl)benzo|DI, 7|naphthyridin-8-yl)umethanol is obtained from tert-butyl 5-(tert-butyldimethylsilyloxy)methyl)-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (Example 99 / Stage 1) and 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile (from of Example 49 / Stage 1), following the procedures described for

Example 44 / Stage 4 and removal of the TV5 group, following the procedure described in Example 99 / Stage 3.

NMR (acetone-av): b 8.79 (5, 1H), 8.73 (5, 1H), 8.35 (y, 1H), 7.61 (5, 1H), 7.33 (y, 1H), 7.09 (a, 1H), 6.75 (a, 1H), 6.68 (ad, 1), 6.57 (Run 5, 2H), 4.47 (0, 2H), 4 .32 (Y, 1H), 3.58 (5, ЗН), 3.17 (I, 2H), 3.04 (y, 2H), 2.30 (in

ZN). GAM5 MANI - 374.2.

Example 109 2-(4-methoxy-2-methylphenethyl)-8-pentylbenzo DI, 7|naphthyridin-5-amine

MN

M | Ma she

Om and

Example 110 8-(2-cyclopropylethyl)-2-(4-methoxy-2-methylphenethyl)benzo (1, 7|Inaphthyridin-5-amine kH,

M | What?

And Ome

Stage 1: tert-butyl 5-bromo-2-chlorophenylcarbamate

The title compound was prepared according to the procedure described in Example 5 / Step 1, but using 5-bromo-2-chloroaniline (commercially available) as starting material. The crude material is purified by flash chromatography on a SOMBIRGAZNO) system (IZSO) using 0-40 96 EIOAc/hexanes to give tert-butyl 5-bromo-2-chlorophenylcarbamate as a pale yellow solid.

Step 2: (E)-tert-butyl 2-chloro-5-(2-cyclopropylvinyl)/phenylcarbamate

A solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (from the previous step) (1.0 eq.) and (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane (commercially available) (1.0 eq) in toluene (0.2 M) was mixed with tetrakis(triphenylphosphine)palladium (5 mol) and 2 M aqueous potassium carbonate (2.0 eq). The reaction mixture is heated to 100 "C and stirred overnight. After cooling to room temperature, the reaction mixture is diluted with EIOAS and water.

The two phases are separated, and the aqueous layer is extracted twice with EOAc. The combined organic phases are washed with saline, dried over anhydrous Md5O»4, and concentrated in vacuo. The crude product is purified by flash chromatography on a SOMVIRGANF system (IZSO) using 0-5595 EOAc/hexanes to give (E)-tert-butyl 2-chloro-5-(2-cyclopropylvinyl)/phenylcarbamate as a pale yellow solid.

Step 3: (E)-tert-butyl 5-(2-cyclopropylvinyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate

The title compound is prepared according to the procedure described in Example 93 / Step 2, but using (E)-tert-butyl 2-chloro-5-(2-cyclopropylvinyl)-phenylcarbamate (from the previous step) as starting material. The crude product is purified by flash chromatography on

SOMVINGA5NE system (IZSO) using 0-10 96 E(OAc/hexanes), which leads to (E)-tert-butyl 5-(2-cyclopropylvinyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl/uphenylcarbamate as a pale yellow solid.

Stage 4: 0 2-(4-methoxy-2-methylphenethyl)-8-pentylbenzo|C(1,7|naphthyridin-5-amine and /- 8-(2-cyclopropylethyl)-2-(4-methoxy-2 -methylphenethyl)benzo|C1, 7UInaphthyridin-5-amine

The title compounds were prepared according to the procedure described in Example 44 / Step 4 (Suzuki Compound) and 5 (reduction), but using (E)-tert-butyl 5-(2-cyclopropylvinyl)-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenylcarbamate (from the previous stage) and 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)-picolinonitrile (from Example 49 / Stage 1) as starting material. The crude product is purified by flash chromatography on a SOMBGABNO system (IZSO) using 0-40 95 EtOAc/hexanes, which gives Example 109 as a white solid: "H NMR (acetone-av): b 8.76 (a, 1H), 8.70 (a, 1Hn), 8.29 (a, 1H), 7.44 (a, 1h), 7.18 (da, 1H), 7.08 ( a, 1), 6.74 (a, 1H), 6.68 (a9, 1H), 6.59 (reg 5, 2H), 3.74 (5, ЗН), 3.18 (i, 2H) , 3.04 (i, 2H), 2.75 (i, 2H), 2.29 (5, ЗН), 1.75-1.68 (t, 2H), 1.40-1.35 (t , 4H), 0.90 (5, ZN); GKM5 |M'NI "- 414.3; and Example 110 in the form of an off-white solid substance: "H NMR (acetone-dv): b 8.76 (a , 1H), 8.70 (a, 1Hn), 8.28 (j, 1 Hn), 7.45 (a, 1), 7.19 (aa, tn), 7.08 (9, 1H), 6.74 (y, 1H), 6.67 (aa, 1H), 6, 55 (Brg 5, 2H), 3.73 (5, ZN), 3.16 (Her, 2H), 3.03 (I, 2H), 2.29 (5, ZN), 1.60 (d, 2H), 1.29-1.28 (t, 1H), 0.89-0.74 (t, 2H), 0.44-0.41 (t, 2H), 0.10- 0.07 ( t, 2H). And AM5 |M-NO - 412.3.

Example 111 (5-amino-2-(2,4,6-trimethylphenethyl)benzo CHY, 7|naphthyridin-8-yl)methanol mno

(5-Amino-2-(2,4,6-trimethylphenethyl)benzo|DI, 7|naphthyridin-8-yl)umethanol is obtained from tert-butyl 5-(tert-butyldimethylsilyloxy)methyl) -2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/phenylcarbamate (from Example 99 / stage 1), 2-ethynyl-1,3,5-trimethylbenzene (commercially available ) and 3-chloro-5-(mesitylethynyl)picolinonitrile (from Example 77 / stage 1), following the procedures described for Example 44 / Stage 4, Example 99 / stage C (removal of TV5) and Example 77 / stage C (reduction) . "H NMR (acetone-dv): b 8.77 (5, 2H), 8.34 (y, 1H), 7.61 (5, 1H), 7.33 (y, 1H), 6.84 (5, 2H), 6.60 (re 5, 2H), 4.77 (0, 2H), 4.35 (Y, 1H), 3.08 (v, 3H), 2.84 (v, 6H ), 2.30-2.29 (t, 4H). And AM5 MANI - 372.2.

Example 112 (5-amino-2-(4-propoxyphenethyl)benzo|D1, 7|Inaphthyridin-8-yl)umethanol

Mn,

M y: 0 o no 7's

(5-Amino-2-(4-propoxyphenethyl)benzo C, 7|Inaphthyridin-8-yl)umethanol is obtained from 8-(tert-butyldimethylsilyloxy)methyl)-3-chlorobenzo C(1,7|naphthyridin-5-amine (from Example 99 / stage 1) and 3-chloro-5-(4-propoxyphenethyl) picolinonitrile (from Example 79 / stage 2) following the procedures described for Example 44 / Stage 4 and Example 99 / stage C (removal of TV5). "H NMR (acetone-dv): b 8.79 (a, 1H), 8.70 (a, 1H), 8.35 (a, 1H), 7.61 (a, 1H), 7.33 ( da, 1), 7.17 (a, 2H), 6.83 (ad, 2H), 6.57 (ri 5, 2H), 4.77 (d, 2H), 4.34 (i, 1H) , 3.89 (i, 2H), 3.22 (i, 2H), 3.06 (i, 2H), 1.83-1.70 (t, 2H), 1.00 (i, ЗН). And AM5 (MANI - 388.2.

Example 113 (2-(2-(1H-indol-5-yl)ethyl)-5-aminobenzo|D|I1, YInaphthyridin-8-ylmethanol

MH,

M | Ma -

F wa no M

Hn (2-(2-(1H-indol-5-yl)ethyl)-5-aminobenzo|DI1, Yanftyridin-8-ylmethanol is obtained from tert-butyl 5- ((tert-butyldimethylsilyloxy)methyl)-2-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenylcarbamate (from Example 99 / stage 1) and 5-(1H-indol-5-yl)ethynyl)-33-chloropicolinonitrile (from Example 44 / stage 3), following the procedures described for Example 44 / Stage 4 and Example 99 / stage C (removal of TV5).

NMR (acetone-dv): b 10.19 (i, 1H), 8.83 (a, 1H), 8.71 (a, 1Hn), 8.35 (a, 1H), 7.60 (j, 1H), 7.46 (a, 1H), 7.36-7.27 (t, ЗН), 7.04 (da, 1H), 6.57 (horn 5, 2H), 6.38 (ai, 1), 4.77 (9, 2H), 4.36 (Y, 1H), 3.29 (y, 2H), 3.19 (y, 2H).

GAM5 MANI - 369.2.

Example 114

M-(4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyluphenyl)acetamide

MN and

F and mn"

Stage 1: M-(4-ethynylphenyl)acetamide

To a solution of 4-ethynylaniline (commercially available) (1.0 equiv.) and triethylamine (1.0 equiv.) in methylene chloride (0.04 M) was slowly added acetyl chloride (1.5 equiv.). The reaction mixture is then stirred at 0 "C for 1 hour. After warming to room temperature, the reaction mixture is diluted with ethyl acetate and water. The two phases are separated, and the aqueous layer is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous Mod5O»4, and concentrated in vacuo. The crude material was purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give M-(4-ethynylphenyl)acetamide as a white solid substances

Step 2: M-(4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)phenyl)acetamide

A solution of 3,5-dichloropicolinonitrile (1.0 equiv), M-(4-ethynylphenyl)acetamide (from the previous step) (1.0 equiv), bis(triphenylphosphine)palladium chloride (10 moles), copper iodide (10 moles), and triethylamine (5.0 eq.) in DMF (0.04 M) were stirred at 60 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated.

The organic layer is washed twice with water, dried over anhydrous Md5O5" and concentrated in vacuo.

The crude material is purified by means of flash chromatography on a SOMBIRGABNO system (IZSO) using 0-80 95 ethyl acetate in hexane, which leads to M-(4-(5-chloro-6-cyanopyridine-3-ylethynyl/uphenyl)acetamide as a white solid matter.

Step 3: M-(4-(2-(5-chloro-6-cyanopyridin-3-yl)ethylphenyl)acetamide

To a solution of M-(4-(5-chloro-6-cyanopyridin-3-yl)ethynyl/uphenyl)acetamide (from the previous stage) in a mixture of ethyl acetate/methanol (1:4, 0.05 M) add 10 95 wt. palladium on charcoal (0.2 equiv.). Hydrogen gas is introduced via a balloon, and the reaction mixture is stirred for 3 hours. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and purified using a SOMVIRI AZNO system (IZSO) using 0-80% ethyl acetate in hexane to give M-(4-(2-(5-chloro-6-cyanopyridin-3-yl)ethyl) )-phenyl)acetamide.

Stage 4: M-(4-(2-(5-amino-8-methylbenzo CY, 7-Naphthyridin-2-yl)ethyluphenyl)acetamide

A solution of M-(4-(2-(5-chloro-6-cyanopyridin-3-yl)uethylphenyl)lacetamide (from the previous step) (1.0 eq.), tert-butyl 4-methyl-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl/uphenyl-carbamate (from Example 5 /

Step 2) (1.5 equiv), tris(dibenzylideneacetone)dipalladium(0) (10 molUb), dicyclohexyl(2,6'-dimethoxybiphenyl-2-yl/phosphine (20 molUb), and potassium phosphate (2, 0 equiv) in n-butanol/H2O (2.5:1, 0.04 M) was stirred at 1002 C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Mod5O»4, and concentrated in vacuo. The crude material was purified by flash chromatography on a SOMBIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane, which leads to the production of M-(4-(2-(5-amino-8-methyl-benzoShrP, 7|Inaphtyridin-2-yl)ethyl)phenyl)acetamide in the form of a white solid. "H NMR (SOCI"): b 8.51 (5, 1H), 8.32 (5, 1H), 8.01 (y, 1H), 7.44 (5, 1H), 7.33-7.36 (t, 2H), 7.03-7.19 (t, ZN), 5.98 (ri, 2H), 3.07-3.11 (t, 2H), 2.94-2.98 (t, 2H), 2, 44 (5, ZN), 2.10 (5, ZN). And AM5 (M ANI - 371.2.

Example 115 methyl 4-(2-(5-amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)ethyl)-3-methylbenzoate

MN, 7 Me

HU to O

F SA OSN, (6;

Stage 1: methyl 3-methyl-4-(triethylsilyl)ethynyl)benzoate

A solution of methyl 4-bromo-3-methylbenzoate (1.0 eq.), triethyl(ethynyl)silane (1.0 eq.), bis(triphenylphosphine)palladium chloride (10 molbb), copper iodide (10 molbb), and triethylamine (5.0 eq.) in DMF (0.04 M) were stirred at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water , dried over anhydrous Md5O5, and concentrated in vacuo. The crude material was purified by flash chromatography on a SOMBIRGAZNO) system (IZSO) using 0-90 ethyl acetate in hexane to give methyl 3-methyl-4-((triethylsilyl)ethynyl )benzoate as a white solid.

Stage 2: Methyl 4-ethynyl-3-methylbenzoate

To a solution of methyl 3-methyl-4-((triethylsilyl)ethynyl)benzoate (from the previous step) (1.0 eq.) in THF (0.2 M), add TVAE (0.2 eq.) slowly at 0 " C. The reaction mixture is then stirred at 0" for 1 hour. After warming to room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO), using 0-80 9o ethyl acetate in hexane, which gives methyl 4-ethynyl-3-methylbenzoate as a white solid.

Stage 3: Methyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate

3,5-dichloropicolinonitrile solution (1.0 eq.), methyl 4-ethynyl-3-methylbenzoate (from previous step) (1.0 eq.), bis(triphenylphosphine)palladium chloride (10 molebs), copper iodide (10 moles), and triethylamine (5.0 eq.) in DMF (0.04 M) were stirred at 60 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated.

The organic layer is washed twice with water, dried over anhydrous Md5O5" and concentrated in vacuo.

The crude material is purified by flash chromatography on a SOMBIGAZNO system (IZSO) using 0-80 90 ethyl acetate in hexane, which gives methyl 4-(5-chloro-6-cyanopyridin-3-yl)/ethynyl)-3-methylbenzoate as a white solid.

Stage 4: methyl methyl 4-((5-amino-1-methylbenzo C(1,7|naphthyridin-2-yl)ethynyl)-3-methylbenzoate

A solution of methyl 4-((5-chloro-6-cyanopyridin-3-yl)/ethynyl)-3-methylbenzoate (from the previous step) (1.0 eq.), tert-butyl 4-methyl-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)uphenylcarbamate (from Example 5 / Stage 2) (1.5 eq.), tris(dibenzylideneacetone)-dipalladium(0) (10 molboo) , dicyclohexyl(2",6'-dimethoxybiphenyl-2-yl/phosphine (20 moles), and potassium phosphate (2.0 equiv.) in n-butanol/H2HO (2.5:1, 0.04 M) are stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous M95O54, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGABNO system (I5CO) using 0-80 95 ethyl acetate in hexane to give methyl methyl-4-((5-amino-8- methylbenzo CI1,7 Inaphthyridin-2-yl)ethynyl)-3-methylbenzoate in the form of a white solid milk substances.

Stage 5: methyl 4-(2-(5-amino-8α-methylbenzo CP, 7Inaphthyridin-2-yl)ethyl)-3-methyl-benzoate

To a solution of methyl methyl 4-((5-amino-8α-methylbenzo H/1,7|Inaphthyridin-2-yl)ethynyl)-3-methylbenzoate (from the previous stage) in a mixture of ethyl acetate/methanol (1:4, 0, 05 M) add 10 95 wt. palladium on charcoal (0.2 equiv.). Hydrogen gas is introduced via a balloon, and the reaction mixture is stirred for 3 hours. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and purified using the SOMVIRIAZNO system (IZSO) using 0-8095 ethyl acetate in hexane to give methyl 4-(2-(5-amino-8- methylbenzo Х1,7|Inaphthyridin-2-yl)ethyl )-3-methylbenzoate. "H NMR (SOSI"): b 8.61 (5, 1H), 8.40 (5, 1H), 8.09 (9, 1H), 7.83 (5, 1H), 7.81 (i , 1H), 7.54 (5, 1H), 7.18-7.20 (t, 2H), 6.17 (rg, 2H), 3.92 (5, ЗН), 3.10-3, 16 (t, 4H), 2.53 (z, ZN), 2.36 (5, ZN). And AM5 (MANI - 386.2.

Example 116 4-(2-(5-amino-β8-methylbenzo DP, 7-Naphthyridin-2-yl)ethyl)-M, 3-dimethylbenzamide mno

M | y: xx - oo

Mu about

Stage 1: 4-(2-(5-amino-8-methylbenzo|CP1, 7YInaphthyridin-2-yl)ethyl)-3-methylbenzoic acid

A solution of methyl /4-(2-(5-amino-1-methylbenzo N(1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoate (with

of Example 115) (1.0 equiv.), and 1 M sodium hydroxide (1.5 equiv.) in methanol (0.04 M) were stirred at 60° for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases are separated. The organic layer is washed twice with water, dried over anhydrous Md5O5, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGA5HO system (IZSO) using 0-50 90 ethyl acetate in hexane to give 4-(2-(5-amino-8-methylbenzo TSI, 7|Inaphthyridin-2-yl)ethyl)-3- methylbenzoic acid in the form of a white solid.

Stage 2: 4-(2-(5-amino-8-methylbenzo|Cl, 7N-naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride

A solution of 4-(2-(5-amino-8-methylbenzoic acid)-3-methylbenzoic acid (from the previous stage) in thionyl chloride is stirred at 60 °C for 3 hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo.The crude material is used in the next step without purification.

Stage 3: 4-(2-(5-amino-8-methylbenzo|CP1, 7N-naphthyridin-2-yl)ethyl)-M, 3-dimethyl-benzamide

To a solution of 4-(2-(5-amino-8-methylbenzo|1,7UInaphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (from the previous stage) (Example 5) and triethylamine (2.5 equiv.) in ether (0.05 M) add methanamine (5.0 equiv.). The reaction mixture is stirred overnight. The reaction mixture is then diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous

M95o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGSABNO system (I5CO), using 0-80 90 ethyl acetate in hexane, which leads to 4-(2-(5-amino-8-methylbenzo|(PC/I1,7|naphthyridin-2-yl)ethyl)-M , 3-dimethylbenzamide in the form of a white solid. "H NMR (SOCI"): b 8.62 (5, 1H), 8.32 (5, 1H), 8.04 (a, 1H), 7.60 ( 5, 1H), 7.46-7.52 (t, 2H), 7.09-7.11 (t, 2H), 6.05 (bg, 2H), 3.09-3.17 (t, 4H), 3.00 (a, ZN), 2.52 (5, ZN), 2.33 (5, ZN). And VM5

IMANNI - 385.2.

Example 117 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide

Mn, 7 | SHE: with -

F KA Fr

To a solution of /4-(2-(5-amino-8-methylbenzo|1,7UInaphthyridin-2-yl)ethyl)-3-methylbenzoyl-chloride (Example 116 / Stage 2) and triethylamine (2.5 equiv.) in M',M',Me-trimethylethane-1,2-diamine (5.0 equiv.) is added to the ether (0.05 M). The reaction mixture is stirred overnight. The reaction mixture is then diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Mo95O4, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMVIRGABNFO system (IZSO) using 0-80 96 ethyl acetate in hexane to give 4-(2-(5-amino-I-methylbenzo CHY, 7|naphthyridin-2-yl) ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide as a white solid. "H NMR (SOSI"): b 8.66 (5, 1Н), 8.37 (5, 1Н), 8.07 (y, 1Н), 7.63 (5, 1Н), 7.09-7 ,30 (t, 4H), 3.90 (rg, 2H), 3.01-3.19 (t, AN), 3.08 (5, 6H), 2.72 (Bg, 5H), 2, 52 (in, ZN), 2.33 (5, ZN). And AM5 (MANI - 456.3.

Example 118 2-(4-methoxyphenethyl)benzo CI, 7|Inaphthyridin-5-amine

MH,

M | and: o

OMe 2-(4-Methoxyphenethyl)benzo SCI, 7|Inaphthyridin-5-amine is prepared from 1-ethynyl-4-methoxybenzene (Example 116 / Stage 2) following the procedures described for Example 45 / Stages 1-3. "H NMR (SOSI"): b 8.69 (5, 1H), 8.47 (5, 1H), 8.27 (y, 1H), 7.80 (y, 2H), 7.58-7 .66 (t, 1H), 7.33-7.42 (t, 1H), 7.15 (a, 2H), 6.90 (a, 2H), 6.25 (rg, 2H), 3, 86 (in, ZN), 3.13-3.23 (t, 2H), 2.97-3.10 (t, 2H). AND AM5 IM.ANI - 330.2.

Example 119 2-(4-methoxy-2-methylphenethyl)benzo|CI1, YInaphthyridin-5-amine

MH,

M | and: o

OMe 2-(4-Methoxy-2-methylphenethyl)benzo|C1,7UInaphthyridin-5-amine is prepared from 1-ethynyl-4-methoxy-2-methylbenzene (commercially available) following the procedures described for Example 45 / Steps 1- 3. 1TH NMR (SOSI): b 8.60 (5, 1H), 8.37 (5, 1H), 8.18 (a, 1H), 7.69 (y, 1H), 7.49-7, 57 (t, 1H), 7.24-7.34 (t, 1H), 6.98 (a, 1H), 6.56-6.70 (t, 2H), 6.00 (BI, 2H) , 3.70 (5, ZN), 3.00-3.09 (t, 2H), 2.83-2.96 (t, 2H), 2.20 (5, ZN). And AM5 (M-NNI - 344 2.

Example 120 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3-methylbenzamide

MH,

M "a xx -

F SA we, 6); 4-(2-(5-Amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)ethyl)-3-methylbenzamide is obtained from 4-(2-(5-amino-8-methylbenzo) ЧИ, 7|Inaphthyridine -2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Step 2) and ammonium following the procedures described for Example 117. "H NMR (SOCI"): b 8.60 (5, 1H), 8 .35 (5, 1H), 8.05 (9, 1H), 7.65 (5, 1H), 7.51-7.53 (t, 2H), 7.13-7.21 (t, 2H ), 3.09-3.16 (t, 4Н), 2.51 (5, ZН), 2.34 (5,

ZN). GAM5 MANI - 371.2

Example 121 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-M, M,Z-trimethylbenzamide mno

M and Ma

F -

F also about 4-(2-(5-Amino-8-methylbenzo|(PCI1,7|naphthyridin-2-yl)ethyl)-M,M,Z-trimethylbenzamide is obtained from 4- (2-(5-amino- 8-methylbenzo DP, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoyl-chloride (Example 116 / Stage 2) and dimethylamine, following the procedures described for Example 117. "H NMR (SOCI"): b 8, 68 (5, 1H), 8.32 (5, 1H), 8.04 (0, 1H), 7.66 (5, 1H), 7.31 (9, 1H), 7.06-7.18 (t, ZN), 3.08-3.19 (t, 4H), 2.96 (a, ZN), 2.54 (5, ZN), 2.33 (5, ZN), 2.05 ( 5, ZN). AND AM5 |MA-NI - 399.2

Example 122 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-M-(2-hydroxyethyl)-3-methylbenzamide

MN"

M | and: with -

Ф ХХ c

ON

Ho) 4-(2-(5-Amino-8-methylbenzo|DC(1,7|naphthyridin-2-yl)ethyl)-M-(2-hydroxyethyl)-3-methyl-benzamide is obtained with 4-(2 -(5-amino-8-methylbenzo HCI, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Step 2) and 2-aminoethanol, following the procedures described for Example 117. "NN

NMR (SOSI): b 8.59 (5, 1H), 8.34 (5, 1H), 8.04 (y, 1H), 7.50-7.62 (t, ЗН), 7.08 -7.25 (t, 2H), 3.60 (i, 2H), 3.63 (i, 2H), 3.07-3.16 (t, 4H), 2.51 (5, ЗН), 2.32 (5, ZN). And AM5 |MA-NI - 415.2

Example 123 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-3-methylbenzamide

Mn, 7th:

J. J

Nn

FI Fi menya 0 4-(2-(5-Amino-8-methylbenzo|(DY1,7|naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-3-methylbenzamide is obtained from 4- (2-(5-amino-1-methylbenzo(DI, 7|naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Stage 2) and M',M'-dimethylethane-1,2- diamine, following the procedures described for Example 117. "H NMR (methanol-dia): b 8.60 (5, 1H), 8.39 (5, 1H), 8.08 (y, 1H), 7.68 (5, 1H), 7.57-7.59 (t, 2H), 7.19-7.22 (t, 2H), 3.57-3.61 (t, 2H), 3.07-3 ,16 (t, 4H), 2.64-2.67 (t, 2H), 2.52 (5, ЗН), 2.38 (5, 6Н), 2.35 (5, ЗН). |MA-NI - 442.3

Example 124 (4-(2-(5-amino-8-methylbenzo|DY, 7-Naphthyridin-2-yl)ethyl)-3-methylphenyl)(pyrrolidin-1-ylumethanone

Mn,

M | Wow

F Fo;

(4-(2-(5-Amino-8-methylbenzo, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl) (pyrrolidin-1-yl)umethanone is obtained from 4-(2-(5-amino -8-methylbenzo DP, 7-Naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Step 2) and pyrrolidine, following the procedures described for Example 117. "H NMR (methanol-da): b 8, 60 (5, 1H), 8.42 (5, 1H), 8.09 (y, 1H), 7.34 (5, 1H), 7.23 (5, 1H), 7.05-7.15 (t, ZN), 3.49 (i, 2H), 3.27 (I, 2H), 3.05-3.17 (t, 4H), 2.42 (v, 3H), 2.26 ( 5, ZN), 1.88-1.91 (t, 2H), 1.73-1.77 (t, 2H). I VM5

IMANI - 425.2

Example 125 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-M-(2-(diethylamino)ethyl)-3-methylbenzamide

MH,

Mt Ve: with -

F Fo: postures o C 4-(2-(5-Amino-8-methylbenzo|DC(1,7|naphthyridin-2-yl)ethyl)-M-(2-(diethylamino)ethyl)-3-methylbenzamide are obtained From 4-(2-(5-amino-8-methylbenzo SHII, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoyl-chloride (Example 116 / Stage 2) and M',M'-diethylethane-1, of 2-diamine following the procedures described for

Example 117. "H NMR (methanol-ad): b 8.55 (5, 1H), 8.48 (5, 1H), 8.10 (a, 1H), 7.56 (5, 1H), 7 ,47-7.50 (t, 1H), 7.33 (5, 1H), 7.10-7.14 (t, 2H), 3.44 (Her, 2H), 5.25 (I, 2H ), 3.08-3.14 (t, AN), 2.62-2.72 (t, AN), 2.42 (5,

ЗН), 2.27 (5, ЗН), 1.05 (I, 6Н). And AM5 IM-NI - 470.3

Example 126 (4-(2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazin-1-yl)umethanone

MH,

M | She:

M. 16); (4-(2-(5-Amino-8-methylbenzo OR, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethyl-piperazin-1-ylumethanone is obtained from 4-(2-(5 -amino-1-methylbenzoic acid, 7Naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Step 2) and 1-ethylpiperazine, following the procedures described for Example 117. "H NMR (Methanol-da) : b 8.59 (5, 1H), 8.37 (5, 1H), 8.06 (y, 1H), 7.32 (5, 1H), 7.00-7.12 (t, 4H) , 3.67 (bg, 2H), 3.06-3.13 (t, 4H), 2.45 (ri, 4H), 2.37 (9, 2H), 2.41 (5, ЗН), 2.26 (5, ZN), 2.19 (horn, 2H), 1.04 (i, ZN).

GAM5IMANI - 468.3

Example 127 (4-(2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)(piperazin-1-yl)umethanone

Mo

Am

M in:

U - (yang ho (c) (4-(2-(5-Amino-8-methylbenzo CH, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl) (piperazine-1-ylumethanone is obtained from 4-( 2-(5-amino-8-methylbenzo HCI, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Step 2) and piperazine, following the procedures described for Example 117. "H NMR ( methanol-а): b 8.66 (5, 1Н), 8.55 (5, 1Н), 8.19 (а, 1Н), 7.38 (5, 1Н), 7.21-7.23 ( t, 2H), 7.10-7.15 (t, 2H), 3.66 (Bg, 6H), 3.08-3.18 (t, 6H), 2.45 (v, ЗН), 2 ,30 (5, ZN). And VM5 (MANI - 440.2

Example 128 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3-methyl-M-(2-(pyrrolidin-1-yl)ethyl)benzamide

MN.

M | SHE:

In -

F Kha styu 16); From 4-(2-(5-amino-8-methylbenzo C(1,7|naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Stage 2) and 2-(pyrrolidin-1-yl) uethanamine, following the procedures described for Example 117. "H NMR (SOCI"): b 8.58 (5, 1H), 8.38 (5, 1H), 8.07 (a, 1H), 7.64 ( 5, 1H), 7.51-7.55 (t, 2H), 7.12-7.20 (t, 2H), 6.26 (ri, 2H), 3.61 (ad, 2H), 3 ,05-3.12 (t, 4H), 2.81 (i, 2H), 2.69 (brg, 4H), 2.50 (5, ЗН), 2.33 (v, ЗН), 1, 83-1.85 (t, 4H). And eM5 |MA-NI - 468.3

Example 129 4-(2-(5-amino-8-methylbenzo DY, Yanaftyridin-2-yl)ethyl)-M-(2-aminoethyl)-3-methylbenzamide

MH,

M | Ve: with -

F ХХ i "it kn,

Ho) 4-(2-(5-Amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)ethyl)-M-(2-aminoethyl)-3-methyl-benzamide is obtained from 4-(2-( 5-amino-8-methylbenzoic acid, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Step 2) and ethane-1,2-diamine, following the procedures described for Example 117. NN

NMR (SOSI"): b 8.59 (5, 1H), 8.37 (5, 1H), 8.07 (a, 1H), 7.63 (5, 1H), 7.51 (Bg, 2H ), 7.12-7.21 (t, 2H), 6.25 (Bg, 2H), 3.48-3.52 (t, 2H), 3.08-3.15 (t, 4H), 2.94 (I, 2H), 2.51 (5, ЗН), 2.34 (5, ЗН). I VM5 | M. ANI - 414 2

Example 130 4-(2-(5-aminobenzo(DI1,7|naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide

MH,

M and She:

THEN

UK

0 4-(2-(5-AminobenzosHI, 7|Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethyl-benzamide is obtained from 4-(2-(5- aminobenzo|CI, 7U|Inaphthyridin-2-yl)ethyl)-3-methylbenzoyl-chloride (Example 116 /

Stage 2) and M',M',Me-trimethylethane-1,2-diamine, following the procedures described for Example 117. H

NMR (methanol-ad): b 8.84 (5, 1H), 8.63 (5, 1H), 8.39 (a, 1H), 7.76-7.83 (t, 2H), 7, 60-7.64 (t, 1H), 7.37 (v, 1H), 7.19-7.29 (t, 2H), 3.96 (I, 2H), 3.48 (I, 2H) , 3.32 (, 2H), 3.20 (i, 2H), 3.09 (5, ЗН), 3.06 (5, 6H), 2.42 (5,

ZN). GAM5 MANI - 442.3

Example 131 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M-methylbenzamide

Mn,

M | in:

4-(2-(5-Amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M-methylbenzamide is obtained from 4- (2-(5-amino-Y-methylbenzo(DI, 7|naphthyridin-2-yl)ethyl)-3-methylbenzoyl-

chloride (Example 116 / Step 2) and M',M',Me-trimethylethane-1 2-diamine, following the procedures described for Example 117. "H NMR (SOCI"): b 8.64 (5, 1H), 8.36 (5, 1H), 8.05 (a, 1H), 7.60 (5, 1H), 7.41 (a, 2H), 7.91 (a, 1), 7.21 (9 , 2H), 3.91 (i, 2H), 3.44 (i, 2H), 3.25 (I, 2H), 3.12 (I, 2H), 3.03 (5, ЗН), 3 .01 (in, 6H), 2.53 (5, ZN). AND AM5 |MA--NI - 442.3

Example 132 2-(4-(2-(5-Aminobenzoxy, Yanaftyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol

Mn,

M She: sh Ba

Ф (АХ on 2-(4-(2-(5-AminobenzoShrP, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)upropan-2-ol was prepared following the procedures described for Example 18, but using methyl 4 -(2-(5-aminobenzo|D(1,7|naphthyridin-2-yl)ethyl)-3-methylbenzoate, which is obtained similarly to Example 115, but using tert-butyl 2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)/uphenylcarbamate u

Stages 4. And EM5 (MANI - 372.2

Example 133 2-(4-butoxyphenethyl)-8-methylbenzo|DI1,7|naphthyridin-5-amine many

Ms. y

Fol 2-(4-Butoxyphenethyl)-8-methylbenzo|C(1,7|Inaphthyridin-5-amine) is prepared following the procedures described for Example 45 / Steps 1-3, but using 1-butoxy-4-ethynylbenzene ( commercially available) with 3,5-dichloropicolinonitrile (commercially available) in step 1. "H NMR (Acetone-dv): δ 8.75 (5, 1H), 8.68 (5, 1H), 8.28 (a , 1H), 7.42 (5, 1H), 7.10-7.18 (t, ZH), 6.84 (9, 2H), 6.58 (rt, 2H), 3.94 (i, 2H), 3.21 (I, 2H), 3.05 (i, 2H), 2.46 (v, ЗН), 1.65-1.75 (t, 2H), 1.41-1.58 (t, 2H), 0.94 (5, ZN). And AM5 |MANI - 386.2.

Example 134 2-(2-(biphenyl-4-yl)ethyl)-8-methylbenzo (1, 7|Inaphthyridin-5-amine many and 2-(2-(Biphenyl-4-yl/ethyl)-8- methylbenzo OR, 7|Inaphthyridin-5-amine is prepared following the procedures described for Example 45 / Steps 1-3, but using 4-ethynylbiphenyl (commercially available) with

with 3,5-dichloropicolinonitrile (commercially available) in Stage 1. "H NMR (Acetone-dv): b 8.80 (5, 1H), 8.75 (5, 1H), 8.26 (a, 2H), 7.55-7.69 (t, 4H), 7.30-7.46 (t, 4H), 7.13 (a, 2H), 6.58 (rg, 2H), 3.30 (1, 2H), 3.18 (i, 2H), 2.45 (5, ZN). I AM5 |MANI - 390.2

Example 135 2-(1,3-dihydroisobenzofuran-1-ylylmethyl)-8-methylbenzo CY, 7-Naphthyridin-5-amine

MH,

M. p

F

Stage 1: 2-((5-amino-Y-methylbenzo DY, 7|naphthyridin-2-yl)ethynylphenyl)methanol 2-(5-Amino-8-methylbenzo CY, 7|naphthyridin-2-yl)ethynyl)phenyl )methanol is prepared following the procedures described for Example 45 / Steps 1-2, but using (2-ethynylphenyl)methanol (commercially available) with 3,5-dichloropicolinonitrile (commercially available) in Step 1. eerg: 2-(1, 3-Dihydroisobenzofuran-1-yl)methyl)-8-methylbenzo| 1, 7UInaphthyridin-5-amine

10 95 mass palladium on coal (0.2 equiv. by mass).

Hydrogen gas is then introduced via balloon, and the reaction is allowed to stir for 18 hours. At this stage, this mixture is filtered through a celite filter, washing with methanol.

Volatiles are removed in vacuo and the resulting residue is purified using a SOMBIGAZNO system (IZSO) using 0-60 9o ethyl acetate in hexanes to give 2-((1,3- dihydroisobenzofuran-1-yl)methyl)-8-methylbenzo | DY, 7UInaphthyridine-5-amine in the form of a solid substance.

IN NMR (Acetone-av): b 8.78 (5, 1H), 8.74 (5, 1H), 8.24 (y, 2H), 7.40-7.44 (t, 2H), 7 ,20-7.34 (t, ZN), 6.61 (Bg, 2H), 5.63-5.69 (t, 1H), 4.89-5.00 (aa, 2H), 3.51 -3.56 (ai, 1H), 3.28-3.34 (ad, 1H), 2.46 (5, ЗН). And AM5

IMANNI - 342.1

Example 136 8-methyl-2-(4-(2-methylallyloxy)uphenethyl)benzo DP, 7|Inaphthyridin-5-amine

MH,

M St

Fa 5 og

Anhydrous potassium carbonate (1 .5 equiv.), followed by metal bromide (1.2 equiv.). The resulting mixture was allowed to stir for 18 hours at 100 "C. After cooling to room temperature, this mixture was diluted with ethyl acetate and water.

The biphasic layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic phases are dried over anhydrous Mag25O4 and the volatiles are removed in vacuo. The resulting residue is purified using the SOMVIRGA5NO system (IZSO), using 0-60 95 ethyl acetate in hexanes, which provides 8-methyl-2-(4-(2-methylallyloxy)-phenethyl)benzo DI, 7|naphthyridine-5-amine in the form of a solid substance. "H NMR (Acetone-av): b 8.75 (5, 1H), 8.68 (5, 1H), 8.27 (9, 1H), 7.41 (5, 1H), 7.12- 7.19 (t, ZN), 6.687 (a, 2H), 6.60 (Bg, 2H), 5.06 (5, 1H), 4.93 (5, 1H), 4.43 (5, 2H ), 3.20 (y, 2H), 3.05 (y, 2H), 2.45 (v, ЗН), 1.79 (5, ЗН). I AM5 |M-ANI - 384.2

Example 137 2-(4-(isopentyloxy)phenethyl)-8-methylbenzo| SCI, 7UInaphthyridine-5-amine

MN

7 2 p

DU

2-(4-(Isopentyloxy)phenethyl)-8-methylbenzo, 7|naphthyridin-5-amine is obtained from 4-(2-(5-amino-8-methylbenzo(SHII1,7|inaphthyridin-2-yl)ethyl) )phenol (from Example 170), following the procedure described for

Example 136, but using 1-bromo-3-methylbutane. "H NMR (Acetone-dv): b 8.72 (5, 1H), 8.69 (5,

1H), 8.26 (a, 1), 7.43 (5, 1H), 7.12-7.18 (t, ЗН), 6.84 (a, 2H), 6.50 (bg, 2H ), 3.98 (i, 2H), 5.21 (I, 2H), 3.06 (I, 2H), 2.46 (5, ЗН), 1.78-1.87 (t, 1H) , 1.61-1.67 (ай, 2Н), 0.96 (в, ЗН), 0.95 (ЗН). And AM5 (MANI - 400.2

Example 138 4-(2-(5-amino-8-methylbenzo DY, 7Inaphthyridin-2-yl)ethyluphenyl-propyl-carbonate

Mn,

M 2nd

Fo about

To a solution of 4-(2-(5-amino-8-methylbenzo DY, 7Inaphthyridin-2-yl)uethylphenol (from Example 170) (1.0 equiv.) and triethylamine (2 equiv.) in dichloromethane (0. 10 M) at 0 "С add ethyl chloroformate (1.2 equiv.). The resulting mixture is left to stir for 30 minutes at 0 "С, after which it is diluted with water and dichloromethane. The two-phase layers are separated and the aqueous layer is washed twice with dichloromethane. The combined organic phases were dried over anhydrous Ma250 and the volatiles were removed in vacuo. - methylbenzoxy, 7Inaphthyridin-2-ylloethylphenyl-ethyl-carbonate in the form of a solid. "H NMR (Acetone-dv): b 8.78 (5, 1Н), 8.73 (5, 1Н), 8.28 ( y, 1H), 7.43 (5, 1H), 7.33 (9, 2H), 7.10-7.17 (t, ЗН), 6.64 (bu, 2H), 4.18 (i , 2H), 3.25 (I, 2H), 3.14 (I, 2H), 2.45 (5, ЗН), 1.68-1.77 (t, 2H), 0.97 (1, ZN). And VM5 (MANI - 416.2

Example 139 ethyl 5-(4-(2-(5-amino-Y-methylbenzo DY, 7|naphthyridin-2-yl)ethyl phenoxy)pentanoate

MH,

M 2 and sa Y o u

Add 60 95 sodium hydride dispersion in mineral oil (1.5 equiv) and the resulting mixture was allowed to stir for 30 min. At this stage, ethyl 5-bromopentanoate (1.2 equiv) was added to this mixture. The reaction mixture was then allowed to stir for 18 hours, after which it is diluted with ethyl acetate and water.

The biphasic layers are separated and the organic layer is washed twice with water. The organic layer was dried over anhydrous MgSO, and the volatiles were removed in vacuo. The resulting residue is purified by HPLC using a gradient of 10-50 96 MesmM in water. The obtained trifluoroacetate salt is then converted into the free basic form using 5iga(o5Zrpege5"M RI-BOZN 5PE ion-exchange resin, which leads to the production of ethyl 5-(4-(2-(5-amino-8-methylbenzo|(DY1,7 |naphthyridin-2-yl)ethyl)phenoxy)pentanoate in the form of a solid. "H NMR (Acetone-av): b 8.80 (5, 1H), 8.74 (c, 1H), 8.33 (9 , 1H), 7.47 (5.1), 7.24 (a, 1), 7.17 (a, 2H), 6.85 (a, 2H), 4.10 (9, 2H), 3 .97 (1, 2H), 3.25 (I, 2H), 3.07 (i, 2), 2.50 (5, ЗН), 2.37 (I, ЗН), 1.74-1, 84 (t, 4H), 1.21 (her, ZN). G AM5 |MNI - 458.2

Example 140 2-(4-(cyclopentyloxy)phenethyl)-8-methylbenzo CI, 7-Naphthyridin-5-amine

MH,

M | SHE:

With o

2-(4--"Cyclopentyloxy)phenethyl)-8-methylbenzo|D(1,7|naphthyridine-5-amine is obtained from 4-(2-(5-amino-8-methylbenzo TSI, 7|Inaphthyridin-2- yl)oethylphenol (from Example 170), following the procedure described for Example 136, but using bromocyclopentane. "H NMR (Acetone-dv): b 8.75 (j, 2H), 8.30 (a, 1), 7 .45 (5, 1H), 7.20 (a, 1), 7.14 (a, 2H), 6.79 (a, 2H), 4.73-4.81 (t, 1H), 3, 22 (i, 2H), 3.05 (b, 2H), 2.47 (5, 3H), 1.85-1.96 (t, 2H), 1.70-1.79 (t, 4H) , 1.56-1.64 (t, 2H). And VM5 (MANI - 398.2

Example 141 2-(4-(cyclobutylmethoxy)phenethyl)-8-methylbenzo| Sh1, 7UInaphthyridine-5-amine

Mn.

M and She:

C o o 2-(4--(Cyclobutylmethoxy)phenethyl)-8-methylbenzo CY, 7Inaphthyridin-5-amine is obtained from 4-(2-(5-amino-8-methylbenzo CY, 7|Inaphthyridin-2-yl) oethylphenol (from Example 170), following the procedure described for Example 136, but using (bromomethyl)cyclobutane. "H NMR (Acetone dv): b 8.79 (5, 1H), 8.73 (5, 1H), 8.33 (y, 1H), 7.47 (5, 1H), 7.26 (a, 1H), 7.16 (a, 2H), 6.82 (9, 2H), 3.90 (9 , 2H), 5.23 (i, 2H), 3.06 (i, 2H), 2.68-2.79 (t, 1H), 2.49 (5, ЗН), 2.05-2, 14 (t, 2H), 1.80-1.98 (t, 4H). AND AM5 MANI - 398.2

Example 142 8-methyl-2-(4-(2-morpholinoethoxy)phenethyl)benzo CHIP, 7|Inaphthyridin-5-amine

MH,

Ah

M | Me c

CA va, 8-Methyl-2-(4--2-morpholinoethoxy)phenethyl)benzo| CI, 7|Naphthyridin-5-amine is prepared from 4-(2-(5-amino-8-methylbenzo) CI, 7|Naphthyridin-2-yl)oethylphenol (from Example 170) following the procedure described for Example 139, but using 4-(2-bromomethyl)morpholine. "H NMR (Acetone-dv): b 8.78 (5, 1H), 8.72 (5, 1H), 8.30 (y, 1H), 7.46 (5, 1H), 7.17-7.24 (t, ZN), 6.85 (9, 2H), 4.08 (i, 2H), 3.56-3.62 (t,

AN), 3.45-3.53 (t, 2H), 3.24 (I, 2H), 3.07 (1, 2H), 2.73 (, 2H), 2.52-2.56 ( t, 2H), 2.49 (5, ЗН). And AM5 |M-NO - 443.2

Example 143 2-(4-(2-(5-amino-8-methylbenzo|D/1,7|naphthyridin-2-yl)ethylphenoxy)-1-phenylethanone

Mn,

M | Ve: p

AI

(c) 2-(4-(2-(5-Amino-8-methylbenzo DY, 7|naphthyridin-2-yl)uethylphenoxy)-1-phenylethanone is obtained from 4-(2-(5-amino-8-methylbenzo DP, 7|Naphthyridin-2-yl)uethylphenol (from Example 170), following the procedure described for Example 139, but using 2-bromo-1-phenylethanone. "H NMR (Acetone-dv): b 8.76 (5 , 1H), 8.71 (5, 1H), 8.27 (a, 1H), 8.06 (a, 2H), 7.67 (I, 1H), 7.57 (I, 2H), 7 .43 (5, 1H), 7.17 (a, ЗН), 6.90 (a, 2H), 5.45 (5, 2H), 3.21 (I, 2H), 3.06 (her, 2H), 2.45 (5, ZN). AND AM5 |MA-NI - 448.2

Example 144 5-(4-(2-(5-amino-8-methylbenzo|(D(1,7|naphthyridin-2-yl)uethylphenoxy)pentanoic acid

MN, 7 | She: p

OA AH aa me

To a solution of ethyl 5-(4-(2-(5-amino-8-methylbenzo| 1, 7U-naphthyridin-2-yl/ethyl phenoxy)-pentanoate (1.0 equiv.)) (from Example 139) in ethanol (0.10 M) anhydrous sodium hydroxide (2.0 equiv.) is added and the resulting mixture is allowed to stir at 80 "C for 2 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate and water. The biphasic layers are separated and the aqueous layer is washed twice with ethyl acetate. The combined organic phases were dried over anhydrous Mag505 and the volatiles were removed in vacuo. The resulting residue was purified using a SOMVIRGASNO system (IZSO) using 0-10 96 methanol in dichloromethane to afford 5-(4-(2-( 5-amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)uethyl)-phenoxy)pentanoic acid in the form of a solid substance. "H NMR (Methanol): b 8.61 (5, 1H), 8 .57 (5, 1H), 8.20 (y, 1H), 7.40 (5, 1), 7.20 (a, 1H), 7.07 (a, 2H), 6.81 (9, 2H), 3.93 (i, 2H), 3.18 (i, 2H), 9.00 (I, 2H), 2.48 (5, ЗН), 2.25 (Ii, 2H), 1, 74-1.81 (t, 2H), 0.8 6-0.96 (t, 2H). And AM5 IMA-NI - 430.2

Example 145 2-(4-(2-(5-amino-8-methylbenzo|PI, 7|naphthyridin-2-yl)uethylphenoxy)ethanol

MN.

And | M. p

F o77-7 oN

Stage 1: 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)phenethyl)-8-methyl-benzo|(DCI1,7|naphthyridin-5-amine 2-(4-(2-("tert-butyldimethylsilyloxy )ethoxy)phenethyl)-8-methylbenzo DP, 7|Naphthyridin-5-amine is obtained from 4-(2-(5-amino-Y-methylbenzo| ЦІ, 7|naphthyridin-2-yl)oethyl phenol (from Example 170), following the procedure described for Example 139, but using (2-bromomethoxy)(tert-butyl)dimethylsilane.

Stage 2: 2-(4-(2-(5-amino-8-methylbenzo| 1, U-naphthyridin-2-yl) uethyl) uphenoxy) ethanol

To a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)phenethyl)-8-methyl-benzo DP, 7UInaphthyridin-5-amine (from the previous stage) (1.0 equiv.) in tetrahydrofuran (0.10 M) a 1.0 M solution of tetrabutylammonium fluoride (5 equiv) in THF is added and the resulting mixture is allowed to stir at 22°C for 2 hours. At this stage, the mixture is diluted with ethyl acetate and water. The biphasic layers are separated and the aqueous layer is washed twice with ethyl acetate. The combined organic phases were dried over anhydrous Ma25O" and the volatiles were removed in vacuo. The resulting residue was purified by the SOMBIRGABNYA! system (IZSO) using 0-10 95 methanol in dichloromethane to afford 2-(4- (2-(5-amino-8-methylbenzol,7|inaphthyridin-2-ylloethylphenoxy)ethanol in the form of a solid substance. "H NMR (Acetone dv): b 8.76 (5, 1H), 8.67 (5 , 1H), 8.28 (9, 1), 7.40 (5, 1H), 7.15 (I, ЗН), 6.84 (a, 2H), 6.54 (re, 2H), 4 ... ,2

Example 146 2-(4-(2-(5-amino-8-methylbenzo|D(/1,7|naphthyridin-2-yl)ethylufenoxy)-M, M-dimethylacetamide

MN, sake and

OO o otry (c)

2-(4-(2-(5-Amino-8-methylbenzo CY, 7|naphthyridin-2-yl)uethylufenoxy)-M, M-dimethyl-acetamide is obtained from 4-(2-(5-amino-8- methylbenzo C1, 7-Naphthyridin-2-yl)ethyl phenol (from Example 170) and following the procedure described for Example 139, but using 2-bromo-M,M-dimethylacetamide.

IN NMR (Acetone-av): b 8.75 (5, 1H), 8.70 (5, 1H), 8.28 (a, 1H), 7.40 (5, 1H), 7.18 (I , 3H), 6.87 (a, 2H), 6.56 (b, 2H), 4.72 (5, 2H), 3.20 (I, 2H), 3.07 (z, 3H), 3 .05 (I, 2H), 2.87 (5, ЗН), 2.45 (5, ЗН). AND AM5 |M--NO - 415.2

Example 147 8-methyl-2-(2-methyl-4-(2-morpholinoethoxy)phenethyl)benzo|D(1,7|naphthyridin-5-amine

Mn, 7 | NOT:

WITH

HA

8-Methyl-2-(2-methyl-4-(2-morpholinoethoxy)phenethyl)benzo|DI1,Yinanaphthyridin-5-amine was prepared following a procedure similar to that described for Example 139, but using 4-(2- (5 -amino-8-methylbenzo|DI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) and 4-(2-bromomethyl)morpholine. "H NMR (Acetone-dv): b 8.73 (y, 2H), 8.26 (a, 1H), 7.44 (5, 1H), 7.17 (y, 1H), 7.05 ( a, 1H), 6.76 (5, 1H), 6.67 (y, 1), 4.04-4.08 (t, ЗН), 3.60-3.62 (t, 4H), 3 .30 (5, 1H), 3.16 (i, 2H), 3.04 (i, 2H), 2.71 i, 2H), 2.50-2.52 (t, 2H), 2.47 (5, ZN), 2.28 (5, ZN). AND AM5 |MA-NI - 457.3

Example 148 2-(2-(4-(2-(5-amino-8-methylbenzoxy, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethanol

Mn,

M | She shchi! that's it

Stage 1: 2-(4-(2-(2-(tert-butyldimethylsilyloxy)ethoxy)ethoxy)-2-methylphenethyl)-8- methylbenzo ЦІ1,7|Inaphthyridin-5-amine 2-(4-(2-( 2-("tert-Butyldimethylsilyloxy)ethoxy)ethoxy)-2-methylphenethyl)-8-methyl-benzo DP, 7U|Inaphthyridin-5-amine is prepared following a procedure similar to that described for Example 145 / Stage 1, but using 4 -(2-(5-amino-1-methylbenzo1,7|naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with tert-butyl(2-(2-chloroethoxy)ethoxy)dimethylsilane.

Stage 2: 2-(2-(4-(2-(5-Amino-8-methylbenzo|CI, 7|naphthyridin-2-yl)ethyl)-3-methyl-phenoxy)ethoxy)ethanol 2-(2- (4-(2-(5-Amino-8-methylbenzo OR, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-ethanol is obtained from 2-(4-(2-(2-(tert -butyldimethylsilyloxy)ethoxy)ethoxy)-2-methyl-phenethyl)-8-methylbenzo OR, 7|Inaphthyridin-5-amine (from the previous step), following the procedures described for

Example 145 / Stage 2. "H NMR (Acetone-ab): b 8.74 (5, 1H), 8.69 (5, 1H), 8.27 (8, 1H), 7.41 (5, 1H ), 7.14 (9, 1H), 7.06 (9, 1H), 6.75 (5, 1H), 6.69 (y, 1), 6.54 (B, 2H), 4.07 (i, 2H), 3.79 (I, 2H), 3.64 (i, 2H), 3.59 (i, 2H), 3.16 (i, 2H), 3.03 (i, 2H) , 2.45 (in, ZN), 2.29 (5, ZN). And VM5 (MANI - 432.2

Example 149 diethyl 3-(4-(2-(5-amino-8-methylbenzo|(DI1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)-propylphosphonate

MH,

M 2

CO

Ov

Oh,

In I

Diethyl 3-(4-(2-(5-amino-8-methylbenzo|(DI1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)-propylphosphonate was prepared following a procedure similar to that described for Example 139, but using 4-(2-(5-amino-8H-methylbenzo[P,7|naphthyridin-2-yl)ethyl)-3-methylphenol (with

Example 50) with diethyl C-bromopropylphosphonate. "H NMR (Acetone-av): b 9.52 (5, 1H), 9.47 (5, 1H), 9.03 (9, 1H), 8.21 (5, 1H), 7.93 ( 9, 1H), 7.84 (a, 1), 7.60 (Bg, 2H), 7.53 (5, 1), 7.45 (a, 1H), 4.76-4.91 (t , 6H), 3.93 (I, 2H), 3.81 (her, 2H), 3.24 (in, ЗН), 3.06 (in, ЗН), 2.76-2.86 (t, 2H), 2.61-2.72 (t, 2H), 2.07 (her, 6H). I VM5

IMANI - 522.2

Example 150 3-(4-(2-(5-amino-8-methylbenzo|1, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonic acid

MH,

M | VE: p

S la

OV,

In (c) a 12 M solution of hydrochloric acid (0.10 M) is added to diethyl 3-(4-(2-(5-amino-8- methylbenzo ХІ1,7|Inaphthyridin-2-yl)ethyl)-3 -methylphenoxy)propylphosphonate (from Example 149) and the resulting mixture is left to stir at 100 "C for 18 hours. At this stage, the hydrochloric acid is removed under reduced pressure and the resulting residue is purified by HPLC using a gradient of 10-50 96 Meskm in water. The resulting trifluoroacetate salt is then converted into the free base form by adding a saturated aqueous solution of sodium bicarbonate, followed by washing three times with ethyl acetate. The combined organic phases were dried over anhydrous MgSO, and the volatiles were removed in vacuo to give 3-(4-(2-(5-amino-8-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl) -3-methylphenoxy)propylphosphonic acid as a solid. "H NMR (Dimethylsulfoxide-α): b 9.72 (Bg, 1H), 9.01 (5, 1H), 8.96 (bBg, 1H), 8.85 (5, 1H), 8.54 ( y, 1H), 7.54 (5, 1H), 7.42 (y, 1H), 7.08 (y, 1), 6.74 (5, 1H), 6.66 (y, 1H), 3.95 (i, 2H), 3.14 (I, 2H), 2.97 (I, 2H), 2.50 (5, ЗН), 2.27 (5, ЗН), 1.81-1 .91 (t, 2H), 1.56-1.67 (t, 2H). And AM5 (MANI - 466.2

Example 151 2-(4-butoxy-2-methylphenethyl)-8-methylbenzo H/1, 7|Inaphthyridin-5-amine

MNO

M 2

FV

Ol 2-(4-Butoxy-2-methylphenethyl)-8-methylbenzo DI, 7|Inaphthyridin-5-amine is prepared following a procedure similar to that described for Example 139, but using 4-(2-(5-amino-8 - methylbenzo ((1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with 1-bromobutane. "H NMR (Acetone-dv): b 8.75 (5, 1H), 8.71 (5, 1H), 8.28 (y, 1H), 7.43 (5, 1H), 7.15 ( a, 1H), 7.07 (a, 1H), 6.75 (5, 1H), 6.69 (yo, 1H), 6.54 (ri, 2H) 3.95 (I, 2H), 3 ,16 (I, 2H), 3.04 (i, 2H), 2.47 (5, ЗН), 2.30 (5, ЗН), 1.69-1.77 (t, 2Н), 1 43-1.54 (t, 2H), 0.97 (I, ZN). I AM5 |(M-NI - 400.2

Example 152 2-(4-(2-(5-aminobenzo DY, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol

Mn,

M | Ka to o7-oN

Stage 1: 4-(2-(5-aminobenzo DY, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenol

4-(2-(5-Aminobenzo DP, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenol was prepared following a procedure similar to that described for Example 145, but using 2-(4-methoxy-2-methylphenethyl )benzo|D(Y1, 7Inaphthyridin-5-amine (from Example 119).

Stage 2: 2-(4-(2-(5-Aminobenzo|DY, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol 2-(4-(2-(5-AminobenzoШЫP, 7|Inaphthyridin) -2-yl)ethyl)-3-methylphenoxy)ethanol is prepared from 4-(2-(5-aminobenzo[Cl,7N-naphthyridin-2-yl)ethyl)-3-methylphenol (from the previous step) following the procedures described for Example 145 / Stages 1-2. | VM5 (MANI - 374.2

Example 153 2-(4-(2-(5-aminobenzoxy, yinanaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol

Mn,

M M

OO UN

Stage 1: 4-(2-(5-Aminobenzo DI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenol 4-(2-(5-Aminobenzo DP, 7|Inaphthyridin-2-yl)ethyl)- 3-Methylphenol is prepared following a procedure similar to that described for Example 50, but using 2-(4-methoxy-2-methylphenethyl)benzo|D(11,7Inaphthyridin-5-amine (from Example 119).

Stage 2: 2-(4-(2-(5-aminobenzo D(1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol 2-(4-(2-(5-AminobenzoShrp), 7| Naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol is obtained following the procedures described for Example 148 / Stages 1-2. | VM5 IM.ANI - 418.2

Example 154 ethyl 5-(4-(2-(5-amino-Y-methylbenzo CHY, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate

Mn,

M M

Hundred years

Ethyl 5-(4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)-pentanoate is obtained from 4-(2-(5-amino -8-methylbenzo|(DI1,7|naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) following the procedure described for Example 139, but using ethyl 5-bromopentanoate. "H NMR (SOSIS): b 8.64 (5, 1H), 8.27 (5, 1H), 8.02 (y, 1H), 7.66 (5, 1H), 7.32 (a, 1H), 6.91 (a , 1H), 6.66 (5, 1H), 6.63 (9, 1H), 4.13 (9, 2H), 3.93 (I, 2H), 3.14 (I, 2H), 2 ... 26 (I, ZN). I AM5 (MANI - 472.3

Example 155 5-(4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoic acid

Mn,

M | In:

5-(4-(2-(5-Amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoic acid is obtained with ethyl 5-(4-(2-(5-amino) -8-methylbenzo DY, 7-Naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate (from the previous step), following the procedure described for Example 144.

NMR (SOSI"): 6 8.52 (5, 1H), 8.27 (5, 1H), 68.02 (a, 1H), 7.65 (5, 1H), 7.32 (a, 1H ), 6.86 (a, 1H), 6.72 (5, 1H), 6.63 (a, 1), 3.95 (I, 2H), 3.15 (I, 2H), 2.99 (I, 2H), 2.54 (5, ЗН), 2.45 (I, 2Н), 2.23 (5, ЗН), 1.79-1.83 (t, 4Н).

IGAM5IMANI - 444 2

Example 156 2-(4-(2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol

MH,

M i z c (Fe o7-oH 2-(4-(2-(5-Amino-8-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol was prepared following the procedures described for Example 145 / Stages 1-2, but using 4-(2-(5-amino-8-methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50). "H NMR (Acetone-dv): b 8.76 (5, 1H), 8.69 (5, 1H), 8.28 (y, 1H), 7.40 (5, 1H), 7.15 (a, 1H ), 7.09 (d, 1H), 6.75 (5, 1H), 6.68 (a, 1H), 6.57 (Bg, 2H), 4.00 (i, 2H), 3.79 -3.88 (t, 2H), 3.17 (I, 2H), 3.04 (i, 2H), 2.46 (5, 2H), 2.29 (v, 2H). I AM5 MANI - 388.5.

Example 157 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyluphenyl-ethyl-carbonate

MH,

M 2

TO od) 4-(2-(5-Amino-8-methylbenzo|(DC(I1,7|naphthyridin-2-yl)/ethyl-phenyl-ethyl-carbonate) is obtained from 4-(2-(5-amino-8- methylbenzo CI, 7|Inaphthyridin-2-yl)oethylphenol (from Example 170), following the procedure described for Example 138, but using ethyl carbonochloridate.

Example 158 methyl 4-(4-(2-(5-amino-8-methylbenzo|ЦІ1, 7ІNaphthyridin-2-yl)uethyl)uphenoxy)butanoate

MH,

M 27 on the left (6;

Methyl 4-(4-(2-(5-amino-8-methylbenzo| DY, 7| naphthyridin-2-yl) ethyl phenoxy) butanoate is obtained from 4- (2-(5-amino-8-methylbenzo DP, 7| Naphthyridin-2-yl)ethyl phenol (from Example 170) following the procedure described for Example 139 but using methyl 4-bromobutanoate. 67 (5, 1H), 8.24 (y, 1H), 7.39 (5, 1H), 7.09-7.19 (t, ЗН), 6.682 (9, 2H), 6.53 (ri , 2H), 3.97 (I, 2H), 3.60 (5, ЗН), 3.19 (i, 2H), 3.04 (i, 2H), 2.48 (I, 2H), 2 .44 (5, ZN), 0.84-0.91 (t, 2H). HeM5 IMNI - 430.2.

Example 159 4-(4-(2-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl)ethylphenoxy)butyric acid

MH,

Mt

CO

F a (c) 4-(4-(2-(5-Amino-8-methylbenzo|(ЧІ1,7|naphthyridin-2-yl)uethylphenoxy)butyric acid is obtained from methyl 4-(4-(2-(5 -amino-8-methylbenzo|DI1,7|naphthyridin-2-yl/uethylphenoxy)-butanoate (from the previous step), following the procedure described for Example 144. "H NMR (Acetone-dv): b 7.47 (5 , 1H), 7.41 (5, 1H), 7.09 (9, 1H), 6.21 (5, 1H), 6.18 (9, 1H), 5.82 (a, 2H), 5 ... 2H), 0.70-0.79 (t, 2H). GAM5 IM-ANI - 416.2.

Example 160 4-(4-(2-(5-amino-8-methylbenzo PI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)butyric acid

Mn,

M M p

SHF or o

Stage 1: methyl 4-(4-(2-(5-amino-Y-methylbenzo CHY, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)butanoate

Methyl 4-(4-(2-(5-amino-β8-methylbenzo DY, 7-Naphthyridin-2-yl)ethyl)-3-methylphenoxy)-butanoate was prepared following a procedure similar to that described for the preparation of Example 158, but using 4-( 2-(5-amino-8-methylbenzo DP, 7-Inaphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50).

Stage 2: 4-(4-(2-(5-Amino-8-methylbenzo H(/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)-butyric acid 4-(4-(2- (5-Amino-8-methylbenzo DI, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyric acid is obtained from methyl 4-(4-(2-(5-amino-8-methylbenzo(DI, 7 |naphthyridin-2-yl)ethyl)-3-methylphenoxy)butanoate (from the previous step), following the procedure described for Example 144.

NMR (Acetone-av): b 8.38 (5, 1H), 8.24 (5, 1H), 7.90 (a, 1H), 6.90 (5, 1H), 6.68 (j, 1H), 6.54-6.63 (t, 2H), b.27 (a, 1), 6.20 (a, 1H), 3.40 (, 2H), 2.62 (i, 2H) , 2.47 (I, 2H), 1.99 (5, ЗН), 1.80 (v, 2H), 1.45 (I, 2H), 1.27-1.39 (t, 2H). And AM5 |MA-NI - 430.2.

Example 161 2-(4-(Isopentyloxy)-2-methylphenethyl)-8-methylbenzo H(1, 7|Inaphthyridin-5-amine

MN",

M sa and 2-(4-(Isopentyloxy)-2-methylphenethyl)-8-methylbenzo Shchy, 7|Inaphthyridin-5-amine is obtained from 4-(2-(5-amino-8-methylbenzo| PI, 7|Inaphthyridin -2-yl)ethyl)-3-methylphenol (from Example 50), following the procedure described for Example 136, but using 1-bromo-3-methylbutane. "H NMR (Acetone-dv): b 8.75 (5, 1H), 8.72 (5, 1H), 8.29 (j, 1H), 7.43 (5, 1H), 7.17 ( 0, 1), 7.10 (a, 1H), 6.76 (a, 1), 6.68 (a9, 1H), 6.56 (Br, 2H), 4.00 (her, 2H), 3.17 (1, 2H), 3.07 (i, 2H), 2.48 (5, ЗН), 1.76-1.91 (t, 1H), 1.60-1.71 (t, 2H), 0.96 (5, 6H).

GAM5 MANI - 414.2.

Example 162 4-(2-(5-amino-β8-methylbenzo DP, 7-Naphthyridin-2-yl)ethyluphenyl-hexyl-carbonate

MN.

М Зо оо 4-(2-(5-Amino-8-methylbenzo|ЦІ1, 7ЯInaphthyridin-2-yl)uethyluphenyl-hexyl-carbonate is obtained from 4-(2-(5-amino-8-methylbenzo| ДІ, 7У |Inaphthyridin-2-yl)ethylphenol (from Example 170), following the procedures described for Example 138, but using hexyl carbonochloridate. And EM5 (MANI - 458.2.

Example 163

2-(2,4,6-trimethylphenethyl)benzo|D|Y1, 7|Inaphthyridin-5-amine

MN, oh

OS

Stage 1: 2-(Mesitythylethynyl)benzo DP, 7|Naphthyridin-5-amine 2-(Mesitythylethynyl)benzo DY, 7|Naphthyridin-5-amine is obtained from 3-chloro-5-(mesitythylethynyl)picolinonitrile (Example 77 / Step 1) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-ylphenylcarbamate (commercially available)) following the procedures described for

Example 45 / Stage 1.

Stage 2: 2-(2,4,6-Trimethylphenethyl)benzo|(DY1,7|naphthyridin-5-amine 2-(2,4,6-Trimethylphenethyl)benzo|DY, 7|Inaphthyridin-5-amine is obtained from 2-(Mesitylethynyl)benzo C1,7|Inaphthyridin-5-amine (from the previous step), following the procedures described for Example 45 / Steps 2-3. "H NMR (Acetone-av): b 8.80 (5, 2H), 8.38 (y, 1Hn), 7.60 (a, 2H), 7.54 (y, 2H), 7.31 (Yii, 1H), 6.84 (5, 2H), 6, 61 (rg, 2H), 3.08 (5, 2H), 2.30 (v, 6H), 2.23 (5, ZN). And AM5 (MANI - 342.2.

Example 164 (5-amino-2-(2,4-dimethylphenethyl)benzo|ЦІ1, 7|Inaphthyridin-8-ylmethanol

Mo

Mt 2 ra no F

Stage 1: methyl 5-amino-2-((2,4-dimethylphenyl)ethynyl)ubenzo DP, 7|Inaphthyridine-8-carboxylate

Methyl 5-amino-2-(2,4-dimethylphenyl)ethynyl)/benzo(CH1,7|naphthyridine-8-carboxylate is obtained from 3-chloro-5-(2,4-dimethylphenyl)ethynyl)picolinonitrile (from Example 47 / Stage 3) and 2-(tert-butoxycarbonylamino)-4-(methoxycarbonylphenylboronic acid) (from Example 85 / Stage 1), following the procedures described in Example 95 / Stage 1.

Stage 2: methyl 5-amino-2-(2,4-dimethylphenethyl)benzo DI, 7|naphthyridine-8-carboxylate

Methyl 5-amino-2-(2,4-dimethylphenethyl)benzo CHY, 7|naphthyridine-8-carboxylate is obtained from methyl

B-amino-2-(2,4-dimethylphenyl)ethynyl/benzo CI, 7U|Inaphthyridine-8-carboxylate (from the previous step), following the procedures described in Example 44 / Step 5.

Stage 3: (5-amino-2-(2,4-dimethylphenethyl)benzo 1,7|naphthyridin-8-yl)methanol (5-Amino-2-(2,4-dimethylphenethyl)benzo DI, 7|naphthyridin- 8-yl)umethanol is obtained from methyl 5-amino-2-(2,4-dimethylphenethyl)benzo HCI, 7|Inaphthyridine-8-carboxylate (from the previous step), following the procedures described in Example 95 / Step 2. "H NMR (Acetone-dv): b 8.79 (5, 1H), 8.73 (5, 1H), 8.35 (9, 1), 7.61 (5, 1H), 7.34 (a, 1H), 7.08 (y, 1H), 6.97 (5, 1H), 6.91 (a, 1), 6.51 (Bg. 2H), 4.77 (5, 2H), 3, 16- 3.20 (t, 2H), 3.04-3.10 (t, 2H), 2.28 (5, ZN), 2.25 (5, ZN). And AM5 (MANI - 358.2 .

Example 165 diethyl 3-(2-(4-(2-(5-amino-8-methylbenzo|D(I1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)propylphosphonate

Mn,

M 2" and o o)

SA about it -- what

Diethyl 3-(2-(4-(2-(5-amino-8-methylbenzo|(DC(1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)-ethoxy)propylphosphonate is obtained following the procedure, described for Example 139, but using 4-(2-(5-amino-1-methylbenzo C1,7|naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 156) and diethyl 3-(2-bromomethoxy) propyl phosphonate and KM5 |MNI - 566.3.

Example 166

Diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo|(ДИ1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)propylphosphonate

Mn,

M 2 vd s with us

OK

Diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)-ethoxy)ethoxy)propylphosphonate is obtained following the procedure , described for Example 139, but using 4-(2-(5-amino-1-methylbenzo C1,7|naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 148) and diethyl 3-(2-( 2-bromomethoxy)ethoxy)propylphosphonate. "H NMR (Acetone-dv): b 8.75 (5, 1H), 8.70 (5, 1H), 8.26 (0, 1H), 7.42 (5, 1H), 7.16 ( 4, 1H), 7.09 (y, 1H), 6.77 (5, 1H), 6.71 (a, 1H), 6.58 (ri, 2H), 3.95-4.11 (t , 6H), 3.76-3.80 (t, 2H), 3.63-3.67 (t, 2H), 3.55-3.58 (t, 2H), 3.57-3.51 (t, 2H), 3.14-3.18 (t, 2H), 3.04-3.05 (t, 2H), 2.46 (5, ЗН), 2.29 (v, ЗН), 1.71-1.87 (t, 4H), 1.22-1.29 (t, 8H). And AM5 (MANI - 610.3.

Example 167 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3-methylphenyl dimethylsulfamate

MN

AH

M 4 and o d

ОХ, 4-(2-(5-Amino-8-methylbenzo|DC(I1,7|naphthyridin-2-yl)ethyl)-3-methylphenyl dimethyl-sulfamate is obtained from 4-(2-(5-amino-Y -methylbenzotriol, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50), following the procedure described for Example 138, but using dimethylsulfamoyl chloride. "H

NMR (Acetone-sv): b 8.79 (5, 1H), 8.72 (5, 1H), 8.28 (j, 1H), 7.42 (5, 1H), 7.27 (a, 1), 7.17 (5, 1H), 7.14 (i, 1H), 7.05-7.10 (a, 1H), 3.19-3.25 (t, 2H), 3.11 -3.17 (t, 2H), 2.92 (v, 6H), 2.46 (5, ЗН), 2.37 (5, ЗН). And AM5

IMANI - 451.2.

Example 168 (5-amino-2-(4-(dimethylamino)phenethyl)benzo HCI, 7Inaphtyridin-8-yl)methanol

MN, as fa

F C. one (5-Amino-2-(4-(dimethylamino)phenethyl)benzo(C1,7|Inaphthyridin-8-ylmethanol) is obtained from tert-butyl 5-(tert-butyldimethylsilyloxy)methyl)-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 99 / step 1) and 4-ethynyl-M,M-dimethylaniline (commercially available) following the procedures described in Example 45 / Stages 1-4 accompanying removal of TV5 group as in

Examples 99 / Stage 3. "H NMR (Acetone-av): b 8.78 (5, 1H), 8.73 (5, 1H), 8.35 (y, 1H), 7.61 (5, 1H ), 7.31-7.35 (a, 1H), 7.08 (9, 1H), 6.68 (a, 2H), 6.50 (Bi, 2H), 4.78 (5, 2H) , 4.34 (5, 1H), 3.16-3.20 (t, 2H), 3.03-3.10 (t, 2H), 2.83 (z, ЗН), 2.80 (5 , ZN). And AM5 (MANI - 373.2.

Example 169 2-(4-(dimethylamino)phenethyl)-8-methylbenzo DI, 7|naphthyridin-5-amine

MH,

Mo M 0, y : x7 2-(4-(Dimethylamino)phenethyl)-8-methylbenzo DY, 7Inaphthyridin-5-amine is prepared following the procedures described for Example 45 / Stages 1-3, but using 4-ethynyl-M . (5, 1H), 7.03 (a, 1n), 6.96 (a, 2H), 6.56 (y, 2H), 6.55 (Run 5, 2H), 3.05 (I, 2H ), 2.88 (i, 2H), 2.75 (v, 6H), 2.33 (5, ЗН). And VM5

IMANI - 357.2

Example 170 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)uethylphenol

Mn,

Mol M ody - he

Step 1: 2-(4-Methoxyphenethyl)-8-methylbenzo|DI1,7|Inaphthyridin-5-amine 2-(4-Methoxyphenethyl)-8-methylbenzo|ЦИ1,ІInaphthyridin-5-amine is prepared following the procedures described for Example 79 / Steps 1-3, but using 1-ethynyl-4-methoxybenzene in Step 1.

Stage 2: 4-(2-(5-Amino-8-methylbenzo (1, 7|Naphthyridin-2-yl)uethylphenol 4-(2-(5-Amino-8-methylbenzo|DI1,7|Naphthyridin-2- yl/ethyl phenol is prepared from 2-(4-methoxyphenethyl)-8-methylbenzo|SHI, 7|naphthyridin-5-amine (from the previous step) following the procedure described for

Example 50. "H NMR (Methanol-Avz): b 8.59

Example 171 1-(4-(2-(5-amino-8-methylbenzo|D/1,7|naphthyridin-2-yl)ethyluphenyl)ethanone

MN, that m

C is 6)

Stage 1: 5-(4-acetylphenyl)ethynyl)-3-chloropicolinonitrile

To a solution of 1-(4-ethynylphenyl)ethanone (commercially available) (1 eq.), 3,5-dichloropicolinonitrile (1 eq.), dichlorobis(triphenylphosphine)-palladium (I) (20 molbb), copper iodide (10 molbb ) and DMF:

Triethylamine (10:1) (0.13 M) was stirred at room temperature overnight. The reaction mixture is then diluted with ethyl acetate and sodium bicarbonate solution. The two phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGAZNO) system (IZSO) using 0-100 96 ethyl acetate in hexane and 5-((4-acetylphenyl)ethynyl)-3-chloropicolinonitrile is isolated as a yellow solid.

Step 2: 5-(4-acetylphenethyl)-3-chloropicolinonitrile

To a solution of 5-(4-acetylphenyl)ethynyl)-3-chloropicolinonitrile (from the previous step) (1 eq.) in ethanol (0.1 M) is added platinum oxide (30 moles). Gaseous hydrogen is introduced using a balloon, and the reaction mixture is stirred for 0.5 hours. This mixture is filtered through a celite filter, washing with dichloromethane. The filtrate is concentrated in vacuo and purified by flash chromatography on a SOMBIRGAZNO system (IZSO) using 0-100 95 ethyl acetate in hexane to give 5-(4-acetylphenethyl)-3-chloropicolinonitrile as an off-white solid.

Stage 3: 1-(4-(2-(5-amino-8-methylbenzo| Х/1, 7UInaphthyridin-2-yl)uethyluphenyl)ethanone

To a solution of 5-(4-acetylphenethyl)-3-chloropicolinonitrile (from the previous stage) (1 equiv.) and tert-butyl

B-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iluphenylcarbamate (1.0 eq.), tetrakis(triphenylphosphine)palladium (10 moles), and 2M an aqueous solution of sodium carbonate (2.0 eq.) in a mixture of toluene/ethanol (1:11, 0.09 M) is heated under microwave conditions using VIOTACE IMITIATOK 2.0 at 1507 C for 20 minutes. After cooling to room temperature, the reaction the mixture was diluted with ethanol/water. The insoluble solid was filtered off and the filtrate was concentrated in vacuo to give a crude residue. The crude material was purified by flash chromatography on a SOMBIRGABNOI system (I5CO) using 0-80 95 ethyl acetate in hexane to give Preparation of 1-(4-(2-(5-amino-8-methylbenzol)C1,7-Naphthyridin-2-yl)/'ethyl)/phenyl)ethanone in the form of a yellow solid. "H NMR (Methanol-dl) TEA salt : b 8.69 (a, 2H), 8.30 (a, 1H), 7.80 (a, 2H), 7.3 8 (c, 1H), 7.36(9, 1H), 7, 28 (9, 2H), 3.25 (I, 2H), 3.13 (I, 2H), 2.47 (5, ЗН), 2.45 (5, ЗН). GAM5 IMANI - 356.2

Example 172 2-(4-((dimethylamino)methyl)phenethyl)-8-methylbenzo| 1, 7|Inaphthyridin-5-amine mno eh M od v

Mu

Stage 1: 4-(2-(5-amino-8-methylbenzo|ЦІ1, 7ІNaphthyridin-2-yl)ethyl)benzaldehyde 4-(2-(5-Amino-8-methylbenzo|DCІ1,7|naphthyridin-2- yl)ethyl)benzaldehyde is prepared from 4-ethynylbenzaldehyde (commercially available) following the procedures described for Example 171 /

Stages 1-3.

Stage 2: 2-(4-(dimethylamino)methyluphenethyl)-8-methylbenzo|D(I1,7|naphthyridin-5-amine

A solution of 4-(2-(5-amino-1-methylbenzo1,7|naphthyridin-2-yl)ethyl)benzaldehyde (from the previous step) (1 equiv.), sodium acetate (3.5 equiv.) and M, M -Dimethylamine hydrochloride (3.5 equiv.), dissolved in 1-2 dichloroethane (0.04 M), is heated at 80"C for 2 hours in a sealed test tube. After cooling to room temperature, the reaction mixture is further cooled to 0 "C and sodium triacetoxyborohydride (1.25 eq.) is added. The reaction mixture was stirred at room temperature for one hour. This mixture is diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Md5O»4, and concentrated in vacuo. The crude material was purified by preparative HPLC using a 10-9095 mixture of acetonitrile/water as gradient and 2-(4-((dimethylamino)methyl)phenethyl)-8-methylbenzo| DI, 7|Inaphthyridin-5-amine is isolated in the form of an off-white powder as a TPA salt. "H NMR (Methanol-da) TEA Salt: b 8.83 (5, 1H), 8.81 (5, 1H), 8.41 (j, 1H), 7.52 (5, 1H), 7, 45 (y, 1H), 7.43 (5, 1H), 7.40 (t, ЗН), 4.29 (5, 2H), 3.30-3.24 (t, AN), 2.79 (in, 6H), 2.60 (5, ZN). AND AM5 |MA-NI - 371.2

Example 173 2-(4-(1-(dimethylamino)ethylufenethyl)-8-methylbenzo|ЦІ1, 7Inaphthyridin-5-amine

Mn that M goes

JSC

2-(4-(1-(Dimethylamino)ethyl)phenethyl)-8-methylbenzo 1, 7 | Inaphthyridin-5-amine is obtained from 1-(4-(2- (5-amino-8-methylbenzo) DY, 7 |Inaphthyridin-2-yl)ethylphenyl)ethanone (from Example 171), following the procedures described for Example 172 / Stage 2. "H NMR (Methanol-diaa) TEA Salt: b 8.84 (5, 1H), 8, 79 (5, 1H), 8.40 (0, 1H), 7.52 (5, 1H), 7.44-7.46 (t, 2H), 7.38-7.42 (t, ЗН) , 4.45 (t, 1H), 3.91 (I, 2H), 3.19 (I, 2H), 2.83 (5, ЗН), 2.66 (5, ЗН), 2.56 ( c, ZN), 1.70 (a, ZN). HeM5 IMA-NI - 385.2

Example 174 1-(4-(2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)ethyl)phenyl)ethanone oxime mno

Mo M

S and

Mu

He

A solution of 1-(4-(2-(5-amino-8-methylbenzo|(DI1,7|naphthyridin-2-yl/ethyl)phenyl)ethanone (from Example 171) (1 eq.), hydroxylamine hydrochloride (2 eq. .) and 1 drop of HOAc dissolved in absolute ethanol (0.028 M) were stirred at room temperature for 1.5 h. This mixture was diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. the combined organic phases are washed with saline solution, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMVIRGABNFO system (I5CO), using 10-80 95 ethyl acetate in hexane, which leads to the preparation of 1-(4-(2-(5-amino-Y-methylbenzo ХІ, 7|Inaphthyridin-2-yl)ethyluphenyl)ethanone oxime in in the form of a white solid. "H NMR (Methanol-α"): b 8.56 (5, 1Н), 8.52 (5, 1Н), 8.12 (а, 1Нн), 7.45 (а, 2Н ), 7.31 (5, 1H), 7.12 (t, ЗН), 4.51 (5, OH), 3.15 (I, 2H), 3.01 (i, 2H), 2.39 (5, ZN), 2.09 (5, ZN). AND AM5 IMA-NI - 371.2

Example 175 8-methyl-2-(4-(methylamino)methyl)/phenethyl)benzo CH, 7|Inaphthyridin-5-amine

MN, my M they are

NM

8-Methyl-2-(4-((methylamino)methyl)uphenethyl)benzo ЧИ, 7|Inaphthyridin-5-amine is obtained from 4-(2-(5-amino-8-methylbenzo ЧИ, 7|Inaphthyridin-2- yl)uethyl)benzaldehyde (from Example 172 / Stage 1) and methylamine, following the procedures described for Example 172, Stage 2. "H NMR (Acetone-iv) TEA

Salt: b 8.95 (5, 1H), 8.88 (5, 1H), 8.43 (y, 1H), 7.58 (5, 1H), 7.54 (y, 2H), 7, 42 (a, 1H), 7.37 (9, 2H), 4.30 (c, 2H), 3.32-3.37 (t, AN), 2.75 (5, ЗН), 2.55 (5, ZN). And AM5 IM-ANI - 357.2

Example 176 (4-(2-(5-amino-8-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)benzylamino)ethanol

Mn that M o re i u

ON

A solution of 4-(2-(5-amino-1-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)benzaldehyde (from Example 172 /

Step 1) (1 equiv.), ethanol-amine (8 equiv.) and 1 drop of HOAc dissolved in absolute ethanol (0.018 M) are stirred at 80 °C for 2 hours. This mixture is cooled to 0 °C and added to Mavnae (3.5 equiv.) and the reaction mixture was stirred for an additional hour at room temperature. This mixture is diluted with ethyl acetate and water. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Mo95O4, and concentrated in vacuo. The crude material is purified by preparative HPLC on a 19 x 50 mm AT AMTIBF 10 micron C18 (Umayeg5 Sogr.) system using 10-90 96 Acetonitrile (0.035 95 TEA) in water (0.05 96 TEA), which leads to a light yellow solid in the form of a TPA salt. "H NMR (Acetone-dv) TRA Salt: b 8.82 (5, 1H), 8.75 (5, 1H), 8.30 (j, 1H), 7.44 (t, ЗН), 7, 28(9, 1H), 7.21 (a, 2H), 4.22 (5, 2H), 3.72 (I, 2H), 3.22 (I, 2H), 3.09 (t, 2H ), 3.07 (I, 2H), 3.01 (65, ОН), 2.41 (5, ЗН), I AM5 IMANI - 387.2

Example 177 8-methyl-2-(4-(pyrrolidin-1-ylmethyl)uphenethyl)benzo PI, 7|naphthyridin-5-amine

MN.

Most of M

8-Methyl-2-(4-(pyrrolidin-1-ylmethyluphenethyl)benzo|DI, 7|Inaphthyridin-5-amine is obtained from 4-(2-(5-

Amino-8-methylbenzo CY, 7|naphthyridin-2-yl)uethyl)benzaldehyde (from Example 172 / Stage 1) and pyrrolidine, following the procedures described for Example 172, stage 2. "H NMR (Acetone-4c) TRA Salt : b 8.88 (5, 1H), 8.82 (5, 1H), 8.82 (5, 1H), 8.43 (j, 1H), 8.38 (9, 1H), 7.58 (5, 1H), 7.51 (t, 1H), 7.33 (y, 2H), 4.16 (5, 2H), 3.32-3.38 (t, AN), 2.55 ( 5, ZN), 2.20-2.32 (t, AN), 1.90-1.99 (t, 4H). G AM5 IM--NI - 397.2

Example 178 2-(3,4-dimethoxyphenethyl)-8-methylbenzo| CI, 7|Inaphthyridin-5-amine

Mn that M

Grandfather

H0) 2-(3,4-Dimethoxyphenethyl)-8-methylbenzo|C(1,7|naphthyridine-5-amine) is prepared from 4-ethynyl-1,2-dimethoxybenzene (commercially available) following the procedures described for Example 45 / Stages 1-3. "H NMR (Acetone-av): b 8.64 (5, 1H), 8.56 (5, 1H), 8.14 (y, 1H), 7.29 (5, 1H ), 7.03 (y, 1H), 6.77 (5, 1H), 6.71 (v, 1H), 6.62 (y, 1H), 6.45 (re, 2H), 3.62 (5, 6H), 3.12 (I, 2H), 2.94 (i, 2H), 2.33 (v, ZN). I AM5 | MANI - 3742

Example 179 2-(1-(4-(2-(5-amino-8-methylbenzo SHY, 7|naphthyridin-2-yl)ethyl)phenyl)ethylamino)ethanol mn, Czech M

Su -- more

ON

2-(1-(4-(2-(5-Amino-8-methylbenzo, 7|naphthyridin-2-yl)ethyl)uphenyl)ethylamino)ethanol (from Example 171) is obtained from 1-(4-(2 -(5-amino-8-methylbenzo(Cl,7|naphthyridin-2-yl)ethyl)phenyl)ethanone and ethanolamine (commercially available) following the procedures described for Example 176. "H NMR (Acetone-abv)

TEA Salts: b 8.78 (y, 1H), 8.29 (y, 1H), 7.83 (5, 1H), 7.45 (t, ЗН), 7.28 (t, ЗН), 4 ,22 (t, 1H), 3.52 (t, 2H), 3.23 (i, 2H), 3.09 (i, 2H), 2.85 (t, 1H), 2.65 (t, 1Н), 2.41 (c, ЗН), 1.61 (а, ЗН). GAM5 |MA-NI - 401.2

Example 180

1-(4-(2-(5-amino-8-methylbenzo|SHI1,7|naphthyridin-2-yl)ethyluphenyl)ethanol

Mn that M

C and on 1-(4-(2-(5-Amino-8-methylbenzo CY, 7|naphthyridin-2-yl)ethyl)uphenyl)ethanol (from Example 171) is isolated as a by-product in the process of reductive amination, as shown in Example 173. "H NMR (Acetone-dv) TEA salt: b 8.90 (5, 1H), 8.88 (5, 1H), 8.42 (a, 1H), 7.57 (5, 1H ), 7.43 (a, 1H), 7.33 (a, 2H), 7.26 (98, 2H), 4.82 (ad, 1H), 3.32 (I, 2H), 3.17 (1, 2H), 3.01 2.55 (5, ZN), 1.41 (5, ZN). And VM5 (MANI - 358.2

Example 181 8-methyl-2-(4-(oxazol-5-ylphenethyl)benzo SHI, 7|Inaphthyridin-5-amine many M ods (A. o

And 7

M

8-Methyl-2-(4-(oxazol-5-ylphenethyl)benzo DY, 7U|inaphthyridin-5-amine was prepared from 5-(4-ethynylphenyl)oxazole (commercially available) following the procedures described for Example 45 /

Stages 1-3. "H NMR (Acetone-dv) TRA salt: 8.69 (5, 1H), 8.59 (5, 1H), 8.16 (j, 1H), 8.04 (5, 1H), 7.55 (t, 2H), 7.38 (5, 1H), 7.28 (t, 2H), 7.01 (t, 2H), 3.16 (, 2H), 3.07 (i, 2H), 2.33 (5, ZN). And AM5 (MANI - 381.2

Example 182 3-(1-(4-(2-(5-amino-8-methylbenzoxy, 7|naphthyridin-2-yl)ethyl)phenyl)-ethylamino)-propanenitrile

Mn, che: M o Dn still

SM

A solution of 1-(4-(2-(5-amino-8-methylbenzo|Cl, 7-Inaphthyridin-2-yl/ethyl)phenyl)ethanone (from Example 171) (1 eq.), 3-aminopropane-nitrile (commercially available ) (2.5 equiv.), dissolved in absolute ethanol (0.014 M), is stirred at 80 "C for 2 hours. This mixture is cooled to 0 "C and added

MasmMVN3 (2 equiv.) and the reaction mixture is stirred for another hour at room temperature. This mixture is diluted with ethyl acetate and ammonium chloride. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases are washed with saline, dried over anhydrous Md5O»4, and concentrated in vacuo. The crude material is purified by preparative HPLC on a 19 x 50 mm AT AMTIBYA 10 micron C18 (Umayeg5 Sogr.) system using 10-90 90 Acetonitrile (0.035 95 TEA) in water (0.05 95 TEA), which gives 3 -(1-(4-(2-(5-amino-8-methylbenzo|DY1,7|naphthyridin-2-yl)ethyl)uphenyl)ethylamino)propanenitrile as a light yellow solid as the TEA salt. "H NMR (Acetone-av): b 8.60 (5, 1H), 8.59 (5, 1H), 8.11 (a, 1), 7.29 (5, 1H), 7.16 ( a, 2H), 7.09 (a, 2H), 7.03 (a, 1H), 6.43 (re, 2H), 3.65 (t, 1H), 3.12 (I, 2H), 2.99 (I, 2H), 2.56 (t, 2H), 2.35 (t, 2H), 2.32 (v, ЗН), 1.16 (y, ЗН).

GAM5 MANI - 410.2

Example 183

(28)-2-(1-(4-(2-(5-amino-8-methylbenzo| DY, 7|Inaphthyridin-2-yl)ethyl)phenyl)-ethylamino)propan-1-ol mn, che M su - that (95! (28)-2-(1-(4-(2-(5-amino-8-methylbenzo|DI, 7|naphthyridin-2-yl)ethyl)phenyl)ethylamino)-propane-1 -ol is obtained from 1-(4-(2-(5-amino-8-methylbenzo| Х/1,7UInaphthyridin-2-yl)ethyl)uphenyl)ethanone (from Example 171) and (K)-2-aminopropane- 1-ol (commercially available) following the procedures described for

Example 182. "H NMR (Acetone-av): 0: 8.94 (t, 2H), 8.45 (t, 1H), 7.64 (y, 2H), 7.59 (5, 1H), 7.55 (Bbg 5, 2H), 7.41 (t, ЗН), 4.65 (t, 1H), 3.81 (t, 1H), 3.35 (Her, 2H), 3.25 ( И, 2Н), 2.56 (5, ЗН), 1.73 (t, ЗН), 1.29 (а,

ZN), 1.23 (a, ZN). G eM5 (MANI - 415.2

Example 184 8-methyl-2-(4-(1-(piperazin-1-yl/uethylufenethyl)benzo CY, Yanftyridin-5-amine)

Mn,

Moss Mu

S and

WITH

M

N

8-Methyl-2-(4-(1-(piperazin-1-yl)u'ethyluphenethyl)benzo OR, 7|naphthyridin-5-amine is obtained from 1-(4-(2-(5-amino-8- methylbenzo|DY, 7|Inaphthyridin-2-yl)uethylphenyl)ethanone (from Example 171) and piperazine (commercially available) following the procedures described for Example 182. "H NMR (Methanol-da) TEA salt: b 8.83 (5, 1H), 8.75 (5, 1H), 8.39 (y, 1H), 7.51 (5, 1H), 7.46 (a, 1H), 7.26 (t, 4H) , 3.62 (t, 1H), 5.25 (i, 2H), 3.12 (Ii, 2H), 2.80 (t, 4H), 2.69 (t, 4H), 2.56 ( c, ZN), 1.42 (a, ZN). GG AM5 IM.ANI - 426.2

Example 185 ((25)-1-(1-(4-(2-(5-amino-8-methylbenzo|CP1, 7|naphthyridin-2-yl/ethyl)phenyl)ethyl)pyrrolidin-2-yl)umethanol

Mn. Czech M v y : that he ((25)-1-(1-(4-(2-(5-Amino-8-methylbenzo ЧИ, 7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)pyrrolidin-2-ylmethanol obtained from 1-(4-(2-(5-amino-Y-methylbenzo D(1,7|naphthyridin-2-yl)ethyluphenyl)ethanone (from

of Example 171) and (5)-pyrrolidin-2-ylmethanol (commercially available) following the procedures described for Example 182. "H NMR (Acetone-dv) TPA salt: b 8.83 (5, 1H), 8.80 (5, 1H), 8.43 (y, 1H), 7.36-7.53 (t, 6H), 4.68 (t, 1H), 3.69 (t, 2H), 3.19- 3.21 (t, 4H), 2.55 (t, 4H), 1.75-1.78 (t, 6H), 1.74 (a, Н). M5

IMANI - 441.2

Example 186

M1-(1-(4-(2-(5-amino-8-methylbenzo|d(1,7|Inaphthyridin-2-yl)ethyl)phenyl)ethyl)-M2,Me-dimethylethane-1,2-diamine

Mn,

Mo M v y

Pho: pocha

M'-(1-(4-(2-(5-amino-8-methylbenzo|DY1,7|naphthyridin-2-yl)uethyl)phenyl)ethyl)-M2,Me-dimethylethane-1,2-diamine is obtained with /1-(4-(2-(5-amino-1-methylbenzo| OR, 7| naphthyridin-2-iluethyl)phenyl)ethanone (with

of Example 171) and M'/M'-dimethylethane-1,2-diamine (commercially available) following the procedures described for Example 182. "H NMR (Acetone-dv) TEA Salt: b 8.85 (t, 2H) , 8.43 (y, 1H), 7.52 (5, 1H), 7.48 (t, 2H), 7.40 (t, 2H), 6.69 (t, 1H), 4.39 ( t, 1H), 3.42 (t, 2H), 3.18-3.25 (t, 6H), 2.67 (5, 6H), 2.56 (5,

ZN), 1.69 (a, ZN). And AM5 | MA-NI - 428.2

Example 187 3-(1-(4-(2-(5-amino-8-methylbenzo|C1, 7|Inaphthyridin-2-yl/ethyluphenyl)ethylamino)propanoic acid

MN, kose Kk

S and

Х in bat he

A solution of 1-(4-(2-(5-amino-8-methylbenzo|(DI1,7|naphthyridin-2-yl/ethyl)phenyl)ethanone (from Example 171) (1 eq.), 3-aminopropanoic acid ( commercially available) (5 eq.), triethylamine (3 eq.), dissolved in absolute ethanol (0.042M) is stirred at 50 °C for 3 hours. This mixture is cooled to 0 °C, and MasMVnHz (1 eq.) is added and the reaction mixture stirred for another six hours at room temperature. Then one more equivalent of MasMmVnH:»z is added and the reaction mixture is stirred at 50 "C for another hour. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and saturated ammonium chloride. The two phases are separated , and the aqueous layer is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous NaCl, and concentrated in vacuo. The crude material is purified by Preparative HPLC on 19 x 50 mm ATI AMTIBO 10 micron C18 (Umayeg5 Sogr.) system using 10-90 956 Acetonitrile ( 0.035 o TEA) in water (0.05 9 TEA), which leads to the preparation of /3-(1-(4-(2-(5-amino-8-methylbenzo|DI1, 7Inaphthyridin-2-yl/uethyl)/ of phenyl)ethylamino)propanoic acid as a white solid as the TPA salt. "H NMR (Methanol-adyaa) TEA Salt: b 8.74 (5, 1H), 8.42 (a, 1H), 7.66 (t, 2H), 7.50 (t, 1H), 7, 91 (a, 2H), 7.23 (t, 2H), 4.24 (t, 1H), 5.21 (i, 2H), 3.14 (i, 2H), 2.75-3.10 (t, 2H), 2.51 (1, 2H), 2.10 (5, ZN), 1.55 (a, ZN). And AM5 (M-NNI - 429.2

Example 188 8-methyl-2-(4-(1-(4-methylpiperazin-1-yl/uethylphenethyl)benzo DI, 7|Inaphthyridin-5-amine)

Mn that M su her i

M. 8-Methyl-2-(4-(1-(4-methylpiperazin-1-yl)ethylufenethyl)benzo C1,7|Inaphthyridin-5-amine is obtained from 1-(4-(2-(5-amino- 8-methylbenzo|DI, 7|naphthyridin-2-yl)ethyluphenyl)ethanone (from Example 171) and 1-methylpiperazine (commercially available) following the procedures described for Example 182. "H NMR

(Acetone-dv) TEA salt: b 8.84 (5, 1H), 8.80 (5, 1H), 8.41 (j, 1H), 7.52 (5, 1H), 7.42-7 ,46 (t, ZN), 7.36-7.38 (t, 2H), 3.53 (t, 1H), 3.18 (t, 2H), 3.12 (t, 2H), 2, 92 (5, 2H), 2.66 (5, 2H), 2.56 (5, 2H), 2.16 (in, ЗН), 1.99 (t, 2Н), 1.69 (y, ЗН ), 1.30 (5, ZN). And AM5 IM-NI - 440.2

Example 189

M2-(1-(4-(2-(5-amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)uethyl)phenyl)ethyl)-M',M'-dimethylpropane-1,2-diamine

MN something M

S and

SYA vky

M2-(1-(4-(2-(5-amino-8-methylbenzo|D1,7Inaphthyridin-2-yl)ethyl)phenyl)ethyl)-M',M'-dimethylpropane-1,2-diamine is obtained from 1-(4-(2-(5-amino-8α-methylbenzo|S/1,7|naphthyridin-2-yl)ethyl)phenyl)ethanone (with

of Example 171) and M',M'-dimethylpropane-1,2-diamine (commercially available) following the procedures described for Example 182. "H NMR (Acetone-dv) TPA Salt: b 8.83 (t, 2H) , 8.40 (a, 1H), 7.46-7.51 (t,

ЗН), 7.43 (t, 1Н), 7.37 (9, 2Н), 4.54 (t, 1Н), 3.74 (t, 1Н), 3.19 (t, 4Н), 2, 90 (5, ZN), 2.77 (5, ZN), 2.55 (5,

ЗН), 2.41 (а, 2Н), 1.66 (а, ЗН), 1.39 (а, ЗН). And AM5 (MANI - 442.2

Example 190 8-methyl-2-(4-(1-(2-(pyridin-4-yl)uethylamino)dethyluphenethyl)benzo DI, 7|naphthyridin-5-amine

Mn,

Mo M v y

With me

8-Methyl-2-(4-(1-(2-(pyridin-4-yl)ethylamino)detylphenethyl)benzo DP, 7|naphthyridin-5-amine is obtained from 1-(4-(2-( 5-Amino-8-methylbenzo|1,7-Naphthyridin-2-yl)ethyl)uphenyl)ethanone (from Example 171) and 2-(pyridin-4-yl)u'ethanamine (commercially available) following the procedures described for

Example 182. "H NMR (Acetone-dv) TEA salt: b 8.94 (t, 2H), 8.92 (y, 2H), 8.73 (5, 1H), 8.43 (y, 1H) , 7.60 (t, 2H), 7.40 (t, 2H), 7.16-7.26 (t, ЗН), 4.55 (t, 1H), 3.55 (t, 4H), 2.56 (t, 4H), 2.12 (5, ZN), 1.73 (a, ZN)

GAM5 MANI - 462.2

Example 191

M1-(1-(4-(2-(5-amino-8-methylbenzo|d(1,7|Inaphthyridin-2-yl)ethyl)phenyl)ethyl)-Me,M2-diethylethane-1,2-diamine

Mn,

Mo M kkd

Pho:

Mt

M'-(1-(4-(2-(5-amino-8-methylbenzo|DY1,7|naphthyridin-2-yl)uethyl)phenyl)ethyl)-M2,Me-diethyl-ethane-1,2- diamine is obtained from /1-(4-(2-(5-amino-1-methylbenzo| OR, 7|naphthyridin-2-iluethyl)phenyl)ethanone (from

Example 171) and M',M'-diethylethane-1,2-diamine (commercially available) following the procedures described for Example 182. "H NMR (Acetone-4c) TEA salt: 0: 8.81 (5, 1H ), 8.75 (5, 1H), 8.23 (y, 1H), 7.60

(a, 2H), 7.39 (9, 2H), 7.28 (t, 2H), 4.51 (t, 1H), 3.82 (t, 1H), 3.62 (t, 1H) , 3.34 (t, 4H), 3.20 (I, 2H), 2.46 (5, ЗН), 2.10 (t, 4H), 1.74 (9, ЗН), 1.34 ( I, 6H). And AM5 (MANI - 456.2

Example 192 2-(4-(Dimethylamino)-2-methylphenethyl)-8-methylbenzo 1, 7|Inaphthyridin-5-amine many

Mo M goes to

Stage 1: 4-iodo-M,M,Z-trimethylaniline

A solution of 4-iodo-3-methylaniline (commercially available) (1 eq.), MnSO 2 (2.5 eq.), and iodomethane (2.5 eq.) in DMF ((0.2 M)) was stirred at room temperature for overnight. The reaction mixture was then diluted with ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography on the SOMVIRGAZNO system (IZSO) using 0-80 9o ethyl acetate in hexane, and 4-iodo-M,M,Z-trimethylaniline is isolated as a yellow solid.

Stage 2: M,M,Z-trimethyl-4-(trimethylsilyl)ethynyl)aniline

A solution of 4-iodo-M, M-3-trimethylaniline (from the previous stage) (1 eq.), ethynyltrimethylsilane (1.5 eq.), dichlorbis(triphenylphosphine)-palladium (II) (20 molybo), copper iodide (20 Molbo) and triethylamine (0.4

M) are stirred at room temperature overnight. The reaction mixture is then diluted with ethyl acetate and ammonium chloride solution. The two phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGA5NO system (IZSO) using 0-100 95 ethyl acetate in hexane, and M,

M,Z-trimethyl-4-(trimethylsilyl)ethynyl)aniline is isolated as a yellow solid.

Stage 3: 4-ethynyl-M,M,Z-trimethylaniline

A solution of M, M-3-trimethyl-4-((trimethylsilyl)ethynyl)aniline (from the previous stage) (1 equiv.), CaCO:3 (2.5 equiv.), in MeOH ((0.15 M) is stirred at at room temperature for six hours. The solid is filtered off and the liquid is concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGA5NO system (IZSO) using 0-80 90 ethyl acetate in hexane, and 4-ethynyl-M, M-Z- trimethylaniline is isolated as a yellow solid.

Stage 4: 3-chloro-5-(4-(dimethylamino)-2-methylphenyl)ethynyl)picolinonitrile

A solution of 4-ethynyl-M,M-3-trimethylaniline (from the previous stage) (1 eq.), 3,5-dichloropicolinonitrile (1.2 eq.), dichlorbis(triphenylphosphine)-palladium (I) (10 moles), copper iodide (10 mol) and DMF:triethylamine (0.28 M) were stirred at room temperature overnight. The reaction mixture is further diluted with ethyl acetate and ammonium chloride solution. The two phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material is purified by flash chromatography on a SOMBIRGABNF system (I5CO) using 0-100 95 ethyl acetate in hexane and 3-chloro-5-(4-(dimethylamino)-2-methylphenyl)ethynyl) picolinonitrile is isolated as a dirty yellow solid substances

Stage 5: 2-(4-(dimethylamino)-2-methylphenyl)ethynyl)-8-methylbenzo|(ЦЙ1,7|naphthyridin-5-amine

A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-iluphenylcarbamate (1.3 eq.) and 3-chloro-5-((4- (dimethylamino)-2-methylphenyl)ethynyl)picolinonitrile (from previous step) (1.0 equiv), tetrakis(triphenylphosphine)palladium (10 molbb), and 2M aqueous sodium carbonate solution (2.0 equiv) in mixture of toluene/ethanol (2:1, 0.17 M) was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with methanol. The insoluble solid was filtered off, and the filtrate was concentrated in vacuo to give a crude residue. The crude material is purified by flash chromatography on a SOMVIBABNFOYA system (IZSO) using 0-80 95 ethyl acetate in hexane, which leads to 2-((4-(dimethylamino)-2-methylphenyl)ethynyl)-8-methylbenzo|ЦІ1, 7Naphthyridine-5-amine as a yellow solid.

Stage 6: 2-(4-(dimethylamino)-2-methylphenethyl)-8-methylbenzo DI, 7|Inaphthyridin-5-amine

To a solution of 2-((4-(dimethylamino)-2-methylphenyl)ethynyl)-8-methylbenzo DI, 7|naphthyridin-5-amine (1 equiv.), (from the previous stage) in a mixture of ethyl acetate/ethanol (1: 5, 0.035 M) add 10 95 wt. palladium on charcoal (0.2 equiv.). Gaseous hydrogen is injected using a balloon, and the reaction mixture is stirred for 3.5 hours. This mixture is filtered through a celite filter, washing with dichloromethane.

The filtrate is concentrated in vacuo and purified using preparative HPLC on 19 x 50 mm

ATI AMTIBZFO 10 micron C18 (Umaieg5 Sogr.) system using 10-90 9o Acetonitrile (0.035 95 TEA) in water (0.0595 TEA), which gives 2-(4-(dimethylamino)-2-methylphenethyl)- 8-methyl-benzo(SHI, Yanftyridin-5-amine in the form of a white solid as a TPA salt. "H NMR (Acetone-dv) TEA

Salt: b 8.81 (5, 1H), 8.74 (5, 1H), 8.34 (y, 1H), 7.89 (5, 1H), 7.47 (t, 2H), 7, 38 (t, 2H), 3.34 (5, 6H), 3.32 (i, 2H), 3.28 (i, 2H), 2.57 (v, ЗН), 2.34 (5, ЗН ). And AM5 MANI - 371.2

Example 193 1-(1-(4-(2-(5-amino-8-methylbenzo|C1, 7|Inaphthyridin-2-yl)uethyluphenyl)ethyl)pyrrolidine-3-carboxylic acid

MN.

Mo M

Dn ud on

Ox 6) 1-(1-(4-(2-(5-Amino-8-methylbenzo OR, 7|naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidine-3-carboxylic acid is obtained from 1-(4 -(2-(5-amino-I-methylbenzo ХІ, 7-Naphthyridin-2-yl)ethyluphenyl)ethanone (with

Example 171) and pyrrolidine-3-carboxylic acid (commercially available), following the procedures described for Example 187, except that in this case, acetic acid is used instead of triethylamine (30 95). "H NMR (Acetone-av) TRA Salt: b 8.81 (5, 1H), 8.75 (5, 1H), 8.70 (5, 1H), 8.28 (a, 1H), 7, 59 (a, 2H), 7.37 (t, ЗН), 4.46 (t, 1H), 4.21 (t 1H), 3.45 (t, 2H), 3.32 (t, 2H) , 3.21 (t, 2H), 3.17 (t, 2H), 2.27 (t, 2H), 2.07 (v, ЗН) 1.77 (0, ЗН). - 455.2

Example 194 4-(1-(4-(2-(5-amino-8-methylbenzo|D1, 7Inaphthyridin-2-yl)/ethyl)phenyl)ethylamino)phenol

МН, ех M 7 и "О он 4-(1-(4-(2-(5-Amino-8-methylbenzo CH, 7|naphthyridin-2-yl)ethyluphenyl)ethylamino)uphenol is obtained from 1-(4- (2-(5-amino-8-methylbenzo|DI,7|naphthyridin-2-yl)ethyluphenyl)ethanone (from Example 171) and 4-aminophenol following the procedures described for Example 187, except that in this case, acetic acid is used instead of triethylamine (28 95). "H NMR (Acetone-Idv) TRA Salt: b 8.83 (5, 1H), 8.73 (5, 1H), 8.33 (j, 1H) , 7.44 (c, 1H), 7.40 (9, 2H), 7.36 (a, 1), 7.24 (a, 2H), 7.10 (a, 2H), 6.76 ( 9, 2H), 4.72 (t, 1H) 3.27 (1, 2H), 3.12 (I, 2H), 2.50 (5, ЗН), 2.06 (a, ЗН). I AM5 |MA-NI - 449.2

Example 195 1-(1-(4-(2-(5-amino-8-methylbenzo|CI1, 7-Naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidin-3-ol

MH,

Mo M v y

СХ СХ on 1-(1-(4-(2-(5-Amino-8-methylbenzo CH, 7|naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidin-3-ol is obtained from 1-(4- (2-(5-Amino-N-methylbenzoyl, 7|Inaphthyridin-2-yl)ethylphenyl)ethanone (from Example 171) and pyrrolidin-3-ol following the procedures described for Example 187, except that in this case, acetic acid is used instead of triethylamine (20 95). "H NMR (Acetone-ydv) TRA Salt: b

8.83 (5, 1H), 8.76 (5, 1H), 8.72 (5, 1H), 8.29 (y, 1H), 7.57 (5, 1H), 7.42 (5 . , 3.19 (t, 2H), 3.10 (t, 2H), 2.10 (c, ЗН), 1.75 (а, ЗН). And VM5

IMANI - 427.2

Example 196 2-(4-(2-aminopropan-2-yl/uphenethyl)-8-methylbenzo (1,7|Inaphtyridin-5-amine

MN.

Mo M - Dn (AH m

To a solution of 4-(2-(5-amino-8-methylbenzo|D(/1,7|naphthyridin-2-yl/uethyl))benzonitrile (from Example 64, stage 1) (1 equiv.), dissolved in dry THF (0.029M), methylmagnesium bromide (6 equiv.) is added very slowly, and the reaction mixture is stirred at room temperature for half an hour. Titanium tetraisopropoxide (3 equiv.) is then added to the reaction flask over ten minutes. The reaction mixture is heated at irrigated for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and saturated ammonium chloride. The two phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Md5bO"4, and concentrated in vacuo.The crude material is purified by preparative HPLC on a 19 x 50 mm AT AMTIBYA 10 micron C18 (Umayeg5 Sogr.) system using 10-90 90 Acetonitrile (0.035 95 TEA) in water (0.05 95 TEA), leading to 2-(4-(2-aminopropan-2-yl)phenethyl )-8-methylbenzo DY, 7|naphthyridine-5-amine as a white solid TEA salt. "H NMR (Methanol-da) TEA Salt b: 9.01 (5, 2H), 8.92 (5, 1H), 8.42 (5, 1H), 7.65 (0, 2H), 7, 56 (in, 1H), 7.39 (t, 2H), 3.19 (t, 4H), 2.54 (5, ЗН), 1.82 (6H). And AM5 (MANI - 371.2.

Example 197

M-(2-acetamidoethyl)-4-(2-(5-amino-8-methylbenzo CY, 7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamide

MH,

M | y: y

Go) n

Fra o N

To a solution of /4-(2-(5-amino-8H-methylbenzo[(/1,7|naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116 / Stage 2) and triethylamine (2.5 eq. .) in ether (0.05 M) was added M-(2-aminoethyl)acetamide (5.0 eq.). The reaction mixture was stirred overnight. The reaction mixture was then diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer extracted twice with ethyl acetate.The combined organic phases were washed with brine, dried over anhydrous

M950o5", and concentrate in a vacuum. The crude material is purified by flash chromatography on

SOMBIRGSABNO system (I5CO), using 0-80 90 ethyl acetate in hexane, which leads to M-(2-acetamidoethyl)-4-(2-(5-amino-8-methyl-benzo|DI,7|naphthyridine-2 -yl)ethyl)-3-methylbenzamide as a white solid. "H NMR (SOSI"): b 8.61 (5, 1Н), 8.38 (5, 1Н), 8.07 (а, 1Н), 7.65 (5, 1Н), 7.51-7 .56 (t, 2H), 7.10-7.16 (t, 2H), 6.25 (Brie, 2H), 3.50-3.59 (t, 4H), 3.08-3.16 (t, 4H), 2.62 (5, ZN), 2.52 (z, ZN), 2.35(5, ZN). And VM5 (MANI - 455.2.

Additional representative compounds of Formula (I) prepared following the procedures described above are presented in Table 1.

Table 1

Number Physical data

Structure M (t/y) (MEN

MN"

M SI

M ve 1 dok 244.0

MN"

M

MB

MN"

Ms. A

K! Ii and 1971

AM

MN"

MU" 4 "DJ o. 2541

MN" where A MY MN ) LF 212,

RI

МН» 24 M Zk li 243.

A-M

MN"

M

M in

MN"

ADAM

M h

МН» m Mach 278.1 and with ko on

MN"

M

MU ia

MN"

M Ma 11 still r 236.2

MN" d M

M. U

12 give 12

MN"

M

MU -

And moshi Shch

MN

M | M 14 yr ON 2821

to me

M

M

MN"

M

M. H

M MN id / x ?

ON, 17 o l 4142

to me

M

M in:

to me

M

M x y o 252

MN"

M | Me E r 3341

MN"

M

MB

MN"

MU and: 22 Zh 304,2

MN

M Mo 23 A r CE, 366.2

MN"

M Mu 24 and r OMe 328.2

MN"

M Me

In r 2361

MN"

M M

26 A r 312.2

MN"

M

MB

MN"

M

M x 28 dO 214.0

IS

MN"

M Me 29 still - 368.1

MN"

GI and: E r 336.1

to me

MU Me, 31 Su r Fe oMe 330.2

MN"

LI Mo 32 r 280.2

MN"

M | M 33 a phi 384.2 ! Co.; -

MN"

M

M Bo from the swarm general

MN" c)

M Me OMe at 2541

MN" (o)

M Mu MnMe 36 Le 2531

MN"

M

We are the UN

МН» g M 38 C 4 2721

MN"

M rav

M Z o)

MN» ball Mu MN

At 21

MN"

And Mach di - 2541

Meo (9)

MN"

LY Mach 42 d 2401 no (in)

MN"

M Mach 43 22 268.1

IR)

F;

MN"

Ot 4 4 Fe 400.2 ma: fi

MN" c)

M

"3 x ОН r 2401

MN (c)

M

46 LY tn r 2241

to me

M M

47 and 1

From -x 310.1

MN"

M | M 48 and 310.1

I Se

MN"

M | where: 49 - 310.1 od and

MN"

M Mu 5O | r 3142

MN"

M Me

BI | r 3142

MN"

M

MB

MN"

M SI

M in: with Do ze

MN"

And | M

Huh

54 F 4342

SK, Fi

MN"

M

55 If 2291 vd

MN"

M | Ma, 56 A 230.0 wk xx 57 is 2641

M M

MN"

MN"

M IF) 58 language 2391 b

ME

M

59 If 21371

MN"

M

If 209,1

MN"

M v1 If 195,1

MN"

M 5 v2 dra 196,

I am 63 m 196.1

M

M Mind

M MN

-sh8- ; olz»zh ih -- M po Shchi

MN"

М 2 че и /х МН» 1 de; chu at 364.5 and / M MN"

O352BO

M y y ru aa; c in 358.4 / in MN" and di 358.4 no B,

IF)

MN"

OS

71 - 348.8 to

SI u l sh i o, i u 348.8

MN"

From 73 he and Still ZA A

In MN" there are -3- 74,348.8 of them

75,263.0 ry

EE MN" 76 so 196.0

Mi ai AM

MN"

MN" in 77 4 C 414.3

Ul Fi c) 78 X s 26vvy

Mr. Ry

MN" 79 |. 212.0

M - M

MN"

ZB cho- -5 and MO Mne 81 Ф Ф 356.2 xx in AM

M

МН ва о 83 Фу ШЫФ 3801

Chh still AM

MN

/ M, MN" is 84 in 370.2

85 SA ge (А 3421

M Am

MN" in

Those (I xx 3681 s AM

M

MN"

MN"

PS

87 4 (From 3421

M MN. / x 7 -- 88 in 356.2

M MN

,/ x 2 nn 7 356.2

F Ge a Z28,1

M - M

MN

M MN

/ x 2 pot 91 d 356.2

МН» i 92 Zh-X S 412.2

Fo eh 93 | DI 3881

FF

M'OSMNn

M MN

/ x 2 94 d 386.2

МН» шча 95 -4 ф 418.2 о и о, I U Ih 496.2

Suz ol x Uh 97 o 450.2 - 5-0 -M Mn x hi o 488.2 chu, 2 | M 456.3 more

UUZUTTO F

MN" dm | M 100 in: f 462.3 inOva (Z

X Phi MN" per 101 in 370.2

WE

102 o Z M 448.6

MN"

Ot --- 103 SHCI C 428.3 (in) - Mo MN y / x ( ? -- M 104 o , sho 412.2

MN"

DM | M

J

105 Phi 440.3

WITH

M MN

- / x 2

LZ

106 and 372.2

to me

DM | M he 107 Fe 414.3

Zh olcho F -- 8i-O -M MN

Shakhova 108, 5BOg2, Z

MN" more;

Mrs. 109 and 4113

Phi U

IN

MN" more; 110 - I 396.2

F. U

- - 111 MN 610.3 2 | in still a

NM

112,355.2 kAM

M

МН» (c) M МН - / х ( ? nado, 113 shko 371.2 va

NM

114,357.2

Am

M

MN"

МН» grya 115 Fo 483.2

Oh s o y

MN"

M Man 116 sh I GU 3422 -M MN --4 117 u 353.2

To us. to me

Me You 118 o and 414.2 y

MN

119 ) (F (F 463.2 lard i"

МН» 120 ОО С Ф 519.2 where U xx | M

SI M

МН ра 1,

M

121 o F F 490.2 dl xx

HU | AM

S M

МН» -M МН» 5-0 122 Mk 396.2 and Со и M МН

MN i x " 123 (7 AL 499.3 and o,

X (c) (c) M MN van / x « 2 124 (7 t- M 443.2 and FO,

MO MN" uh / x " no - 125 U s shk 485.3 on zle Y -M MN"

MN X / M 126 M 4292 and g -M MN

X x 127 310.2 no -M MN"

H. U

128 no 338.2 o no i

MN" 129th. 380.3

SK AJ

130 and 300.1

Mrich

MN"

M o / m, MN" in, x that 181 o she 430.2 but -M MN" ih l, 132 in 402.2

MN" 27 M 133 B S 416.2 on Photo

MN" 2 | M s 134 Ff 458.2 ports Fe is;

M Mn / x? 5-0 135 (Z 3742 -ksh Mn, o X i, 136 3 392.1

MN

M- 137 - 304.0

Vg HM 9

And

Re

EX

138 | and: 3342

M - M

MN" at 9 a.m. 3141

There is AM

M

MN

E Z h F 140 y: Another 3141

M AM

MN" "o -9 141 Me She 3141

M AM

MN"

hee

Sh 142 | and 3021 dk AM

M

MN"

Хх хх 143 | 220.1 li

M AM

MN" in FI 144 Still Z18y

M M

MN"

E and Phi yah Phi uv

M M

MN" and Fi 146 | and: 3181

M - M

MN" 5

F xx 147 | . 306.1

M --M

MN» rah hu 148 o Ti 268, rya

M M

MN"

Mne u 149 o) y 2821 y xx 15O no Ti 226 p

M - M

МН» 151 o h o 328.2

M AM

Mn

SEVEN

152 M 2441 rij

M SMno va 153 M 328.2 y

M SMmn

ST o g 154 re ЗB

FFff

M SMn

Fu - 155 o 7 356.2

AM

FF

M SMNY"

Mo MN / x 2 li

M

156 in 342.2

Mo MN / x 2 nn

M

157 in 342.2

Mo MN / x 2

Wow

M

158 r, 5 3121

Mo MN / x 2 nIDDH

M

159 (7 5 342.2

Mo MN / x 2 ih

M

160 (and t. 3142

Mo MN t / x 2

OA

161 5 353.2

Yaru g 162 ml 2801 rya

M'OSMN"

M MN

/ x 2 o) -sh Me 163 -/ 282.2

SI and 164 | 2581

My dream

M'OSMNh

MN"

DM M

165 x 283.1

OHM

Mo Mne o / x ( - M 166 /9 o 382.2 ipi y,

MN" 167 9 |, 316

With c)

Mo MN / x 2 o) - Me 168 and 2841 -M MN,

NI X h o- M 169 r o 325.2

MN» schi; 170 r 2531

An - M to me

X kva; 171,315.2

NM and 172 Her, 239.1 ry

M'OSMN" p. 173 I 293.2

My dream

M'OSMN"

o- Mo MN / x 2 174 375.2

ZMU x 175 In 253 ry

M'OSMNh -

MN

Uh 176 Central Committee 2391 o

M'OSMNh

MN» dm in 177 279.2 he i, -M MN

OoO- 178 OH Z 330.2

MN"

DM M

179 that 2531

NoM

NM. 2 МН 2 180 И 2401 -

M'SMNY

MN" dm you 181 that 282.2 no

M MN

/ x 2 no 183 YAZ 8 362.2 names

Fe

M СМн» -- Mn;

M- X M 184 1 / 343.2

M MN

/ х 2 их что - 185 х 345.2 но - МН

X is given; 186 in 386.2 - M

NM h o i; and M 187 - 345.2 - Mn, -M X x but M 188 mae Sh and 189 ShCHA 260.1

Fffff

M Mn m (7 MN" x pkandev; 190 t 398.1 -M MN" 03 MY 191 5 3542 192 F y | C 340.2 is M

MN"

NO - KM MN"

X X lat 193 5 398.2

MN" i M 194 skh (i 442.2

F le - IF)

OO more

Ek AM 195 NM M 323.2 re y

More

AM

196 2361 rya

M'SMNY

More

AM

197 22171 rya

M M'OSMN"

NhM -M 198 m-- / 2641

We

NhM -M 199 m-- / 250.1

Hm

NM

-M 200 no / 2641

HM and

NhM -M 201 M-- / U 2981 a,

MN" tv 202 - 366.2 years

F. U

Nm -M 203 -- 266.2

Hm

NM

-M 204 M-- / 262

M

MN I 205 4 C 368.2

F U eh

M

206 g 2 1971 rya ant MN"

OO lne

J

207 M z01y / xx -m

MN"

OO

208 -4 Another 388.2

Also about

More

А-М 203 241 -6. 2

M M' CM,

OO xx 210 | 2441 dk AM som

MN"

Not -M 211 M o- 288.1 s-4 - OO

Not -M 212 M o-- 2721

E / - OO 2 SI

M

213,275.0 o. 2 m M sMnb

OO

NOM

-M 214 H 260.1 sI-i

MES

/ x 2 a 215 Z 330.2

ON

- Neo cha 216 (7 346.1

E p ozhe - Ne pol 217 Fi 391,2

MN" dm | M 218 Same C 405.2

I and

BUT and M

MN" rya 219 4 C 405.2 and i vsaa

Hmmm

AND; 220 -4 in 488.3 /

Od, sh / o

Mo MN / x 2 i-3-- 221 (U 3742 on on on 222 316.2 kA

M

MN"

SOOT

223 | 330.2

МН» 224 in g at 328.2

M A-M

MN"

M MN

/ x 2 nn

M

225 in 3422 o Shchi 226 | B 343.2 dk AM

M

MN» sl 227 si s FI 383.2 iya -M

MN"

M MN

/ x 2 d

M

228 in 370.2

Mo MN / x 2 ih oo 229 t 397.2

Mo MN / x 2

X ND

IF) M 230 in 3442

In Mo MN / x 2 shk oz! with z -y a,

Mo MN / x 2 xx s i 232 382.2 shk a,

AI:

Mo MN / x 2 ii 233 and 318.2

M

M MN nOo-mn lk t aly 234 NM 5 372.2

Mo MN / x 2 s / hk ---- 235 in 339.2

In the Ministry of Defense of the Republic of Belarus

M / x ( 236 U M 427 2

Mo MN / x 2 uk "(3-7 237 5 329.2

MN M MN ana 238 t 371.2

MN / t 239 Z 461.3

M M MN

XX / x x 2

Sh 240 t 353.2

241 « in -- in 411.2

M ХМ и гл,

With 0, 242 - um 427.2

M WHAT d-Al,

MN" 243 F | ch C 443.2

Am

M

MN"

MN

244 F F 371.2 in:

M AM

MN"

МН» 245 Z | Ex with 357.2

M M

МН» r V, 246 X -- IM 441.2

M. H. M. and

AT-

M MN

/ x ?

Oh

M

247 g - 433.2

Example 198

Ip mimo The effectiveness of compounds in increasing the immune response

In order to demonstrate the ability of the compounds disclosed herein to enhance the immune response to a bacterial antigen when the antigen is administered to a subject, the three compounds are used in combination with a recombinant M. teipoiidiae serogroup B vaccine. The vaccine, which is fully described in

Sishiiapi eyi aI. (2006) Rgos Mai! Asai bsi OO 5 A 103(29):10834-9 and MUMO2004/032958 - referred to herein as "ZMepV" - investigate ip mimo in mice with either ME59 or ME59 and one of the compounds disclosed herein. Mice are immunized with two doses administered intramuscularly, with

ZMepB/ME59 is one of the six compounds or, as a positive control, the amount of Cpo oligonucleotide (Cpo"), 848, or Ittidcytoa (Itib)). An additional positive control is ZMepB/ME59-OMMU (vesicles of the outer membrane obtained from M. tepipoiidiae serogroup B strain M298/254) are also compared.

The titer of serum bactericidal antibody ("SBA") is examined two weeks after the second dose, using the standard SPO method or the Alitag Vise method, using M. tepipouilai serogroup strain M298. The 5BA titer is an EBA/EMEA accepted surrogate marker for the effectiveness of M. tepidoiia5 vaccines in humans. The results are shown in Figure 1 (with the compound dose in μg shown on the left). The fold change relative to the response induced by ME59/3MepB is shown to the right of each bar in Figure 1.

In the second experiment, the dose response of one compound, Example Mo. 47, are tested using the same protocol. Figure 2 shows the mean of three independent 5VA studies with standard deviation shown as error bars. 5BA titers are measured in all cases using the standard SRISH method. The dose of each compound in µg is shown on the left of Figure 2.

Figure C shows the 5BA titers of two independent studies comparing the dose response to the compound of Example Mo. 47 with ZMepV with alums added as adjuvant instead of ME59 adjuvant.

Figure 4 shows the 5BA titers of another study comparing the dose response to another compound,

An example of Mo. 169.

Figure 5 summarizes data from six general experiments. A titer of » 1000 correlates with immunization providing protection against the pathogen tested in the ZBA titer (i.e., M. tepipoiidiae serogroup B strain

M27/98). Thus, at 100 μg, each of the compounds of Example Mo. 47, Example Mo. 169, and Example

Mo. 49 is capable of eliciting a protective response in mice, thus demonstrating the ability of the compounds disclosed herein to enhance the immune response to an antigen. Only one of six experiments using ZMepB/ME59 provided a protective response against M298 bacteria. In comparison, seven out of eight experiments using the compounds disclosed herein provided a protective response against M298 bacteria. "" and " above a compound in Figure 5 indicates a statistically significant difference in p-value between immunization with the compound and immunization without the compound (ie, compared to

ZMepV/ME59 control). p5 - shows that the difference is not statistically significant according to the p-value.

Immunization with Cro oligo in comparison with the compound of Example Mo. 47 does not create a statistically significant difference according to the p-value.

Body weights of mice are measured at early (day 1 and day 2) and late (day 14 and day 28) time points after immunization. Immunization with ZMepV/ME59 in comparison with ZMepV/ME59 same Example Mo. 169 does not create a statistically significant difference in mass loss. Mice immunized with Cro oligo or with ZMepv/OMM show a slight but statistically significant decrease in weight on day one after immunization.

Research

Compounds of Formula (I) provided herein are tested to measure their ability to modulate Toll-like receptors.

Study of human peripheral blood mononuclear cells

The bioactivity of the described compounds is tested in the study of human peripheral blood (human PBMC) using a group of independent normal human donors in accordance with the instructions approved by the departmental supervisory committee. Human PBMCs are isolated from fresh peripheral blood using a ficoll concentration gradient (CE Peipsage 17-1440-03). 30-35 ml of human peripheral blood are added to 15 ml of ficol in 50 ml conical flasks, followed by centrifugation at 1800 rpm. (Errepaogii Sepigiides 5810K with biohazard caps on tubes) at room temperature for 30 minutes without acceleration or deceleration. The leukocyte films are then collected and transferred to new 50 ml conical flasks and washed twice in complete medium consisting of KRMI 1640 (11875085 from Ipmigodep Sogrogaiyop, Sagizride, Saiyogpia) supplemented with 10 95 heat-inactivated fetal bovine serum (bibso 10099-141), 1 95 penicillin-streptomycin ((irsof15140-122), 1 mM non-essential amino acids ((zirsozh11140-050), 1 mM sodium pyruvate (5ibsoy 1360-0700), 2 mM I-glutamine (sirsoy 25030-081) and 1 mM NEREZ ( sirsof1 5630-080). Viable cells are then counted using triptan blue staining, placed in 96-well flat-bottomed plates (Vesiop bisKipbop Zh353070) at a density of 2 x 105 cells per well in 200 μl total volume of complete medium. Then compounds are added in in a 10-point dose-response format, starting at 100 μM, 3-fold dilution. An equal concentration of HOM5O is added to negative control wells. Culture supernatants are collected after 18-24 hours of incubation at 37 "C, 5 95 СО", store at -20 "С until further use.

I--6 levels in culture supernatants are measured using the I itipekh kit (Viogai).

The analysis data are presented using the Rgicht software from sgarpRaa (Zap Oiedo,

SA). Dose-effect curves are constructed for each compound and the EC50O value is defined as the concentration that has 50 95 of the maximum signal.

Reporter gene studies

Human Wolffian body 293 (HEC 293) cells are stably transfected with TI K7 or

Human TIK8 and ME-KV-directed luciferase reporter gene (rmipu-I isitegase). As a control study, normal Nek293 transfected with rmiyu-

H. Cells are cultured in OMEM supplemented with 2 mM I-glutamine, 10 95 heat-inactivated

EB5, 195 penicillin and streptomycin, 2 μg/ml puromycin (Iplimobep and Zhapi-ri-5) and 5! µg/ml blasticidin (Ipmygodep Zh46-1120). Hydronpi-SiO" M luciferase assay buffer and substrate are supplied by Rgoteda ZHE263B and 2E264B (assay substrate and buffer, respectively). The 384-well plates with a clear bottom are supplied by Siegipeg Bio-ope (25789163-5) and are OME special plates with bar- by code

Cells are placed at a density of 25,000 cells/well in 384-well plates in a final volume of 50 μl of medium. Cells are allowed to attach to the plates after being cultured overnight (18 hours) at 37°C 595°C. Serially diluted experimental and positive control compounds are then dispensed into each well and incubated for 7 hours at 37°C 5595°C. Cells stimulated with OM5O alone also serve as negative controls. After incubation, 30 μl of premixed assay buffer and substrate buffer are added to each well according to the manufacturer's instructions. The luminescence signal is read on a SIIRK device with an integration time of 20 seconds per tablet.

Dose-effect curves are constructed for each compound and EC5O values are defined as the concentration that has 50 95 of the maximum signal.

Determined research results

Various compounds of Formula (1I)-(XMI) in free form or in the form of a pharmaceutically acceptable salt, have pharmacological properties, for example, as shown by means of ip migo studies described in this application. EC values in these experiments are presented as the concentration of the test compound under consideration that elicits a response that is intermediate between the baseline and maximal responses. In certain examples, the compounds of Formula (1)-(XMI) have an EC value of 1

NM to 200 µM. In some examples, the compounds of Formula (1)-(XMI) have EC values from 0.01 µM to 100 µM. In other examples, the compounds of Formula (1)-(XMI) have ESbvho values from 0.01 µM to 50 µM.

In other examples, the compounds of Formula (1I)-(XMI) have EC values from 0.01 µM to 25 µM. In other examples, the compounds of Formula (I)-(XMI) have EC values from 0.01 µM to 20 µM. In other examples, the compounds of Formula (I)-(XMI) have EC values from 0.01 µM to 15 µM. In other examples, the compounds of Formula (I)-(XMI) have EC values from 0.01 µM to 10 µM. In other examples, the compounds of Formula (1I)-(XMI) have EC values from 0.01 µM to 5 µM. In other examples, the compounds of Formula (1I)-(XMI) have ESvho values from 0.01 µM to 2 µM. In other examples, compounds

Formulas (1)-(XMI) have an EC value from 0.01 µM to 1 µM. In certain examples, such ESvo values are obtained in relation to the activity of the resiquimod dial up to 100 95.

In other examples, the following compounds of Formula (1I)-(XMI) have ESvho values from 1 nM to 200 μM: 2- methylbenzo SHI, 7|Inaphthyridin-5-amine; 2-Propylbenzo OR, 7|Inaphthyridin-5-amine; 2- ethylbenzo DP, 7-Naphthyridin-5-amine; 2-(3-Methoxyphenethyl)benzo CI, 7|Inaphthyridin-5-amine; 8-methylbenzol/1,7|inaphthyridin-5-amine; 8-methyl-2-phenethylbenzo| 1, 7UInaphthyridin-5-amine; methyl 5-aminobenzo| 11, 7UInaphthyridine-Z-carboxylate; (5-aminobenzoic acid, 7|naphthyridin-3-yl)umethanol; benzo DP, 7UInaphthyridin-5-amine; (5-aminobenzo|DI1,7|naphthyridin-8-yl)methanol; 2-(2-methylphenethyl)benzo|D(1,7UInaphthyridin-5-amine;. 2-(3-methylphenethyl)benzo|D(1,7|naphthyridin-5-amine; 2-(4-methylphenethyl)benzo| DY1,7|Inaphthyridin-5-amine; 8-chlorobenzo SHI, 7Inaphthyridin-5-amine; ethyl 5-aminobenzo| 11, 7UInaphthyridine-9-carboxylate; 8-methoxybenzo| 1, 7)|Inaphthyridin-5-amine; 8 - (trifluoromethyl)benzo(ЦІ1,7|naphthyridine-5-amine; 8-fluorobenzo|DC11,7|naphthyridine-5-amine; 3- methylbenzo SHІ, 7|Inaphthyridin-5-amine; Z-fluorobenzo| 1, 7Inaphthyridine -5-amine; 2-phenethylbenzo|1, 7-Naphthyridin-5-amine; 8-methyl-2-(2-(naphthalen-1-yl)uethyl/ubenzo CH, 7|naphthyridin-5-amine; 8-methyl- 2-(2-(naphthalen-2-yl)uethyl)ubenzo DI, 7naphthyridin-5-amine; 4-(2-(5-amino-8-methylbenzo(SHII1,7|Inaphthyridin-2-yl)ethyl)benzoin acid; 3-(2-(5-amino-8-methylbenzo(SHII1,7|Inaphthyridin-2-yl)ethyl)benzoic acid; 2-(z-chlorophenethyl)-8- methylbenzo Х/1,7|Inaphthyridin- 5-amine; 2-(2-chlorophenethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine; (3-(2- (5-amino-8-methylbenzo| DI, 7|Inaphthyridin-2-yl) ethylphenyl)methanol, 2-(4-chlorophenethyl)-8-methylbenzo SHII, 7| Inaphthyridin-5-amine; 2-(4-butylphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-butylphenethyl)-8-methylbenzo DP, 7-Naphthyridin-5-amine; 2-(4-propylphenethyl)benzo|DI1,7|naphthyridin-5-amine; 2-(4--"trifluoromethyl)phenethyl)benzo OR, 7|Inaphthyridin-5-amine; 2-(2,5-dimethylphenethyl)-8-methylbenzo Х/1,7|Inaphthyridin-5-amine;. 8-methyl-2-(4-propylphenethyl)benzo or 7|Inaphthyridin-5-amine; 8-methyl-2-(2,4,5-trimethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; 2-(2,5- dimethylphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-isopropylphenethyl)-8-methylbenzo Х/1,7|Inaphthyridin-5-amine;. 2-(4-hepgylphenethyl)-8-methylbenzo DY, 7|naphthyridin-5-amine; 2-(4-isobutoxyphenethyl)-8-methylbenzo|DC(I1,7|naphthyridin-5-amine; 2-(4-(2-methoxyethoxy)methoxy)phenethyl)-8-methylbenzo| 1, 7UInaphthyridin-5-amine; 8-methyl-2-(4-(2- phenoxyethoxy)phenethyl)benzo SHI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(4-phenylbutoxy)phenethyl)benzo|C1, 7|Inaphthyridin-5-amine; 2-(4-(allyloxy)phenethyl)-8-methylbenzo SHI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(3-

phenylpropoxy)phenethyl)benzo| DY, 7|naphthyridine-5-amine; 2-(4-(heptan-4-yloxy)phenethyl)-8- methylbenzo SHHI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(4-methylpent-3-enyloxy)phenethyl)benzo CI, 7-Naphthyridin-5-amine; 2-(4-(2-Cyclohexylethoxy)phenethyl)-8-methylbenzo SHHI, 7|Inaphthyridin-5-amine; 2-(4-isopropoxyphenethyl)-8-methylbenzo| DY, 7|naphthyridine-5-amine; 2-(4-(3,3-dimethylbutoxy)phenethyl)-8-methylbenzo CY, 7-Naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(4-(dimethylamino)phenethyl)benzo (1, 7|Inaphthyridin-5-amine; 8-(2-cyclopropylethyl)- 2-(2,4-dimethylphenethyl)benzo DP, 7|Inaphthyridin-5-amine; IM-(4-(2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethyluphenyl)acetamide; M-(4-(2-(5-aminobenzo |DY1,7|naphthyridin-2-yl)ethyl)phenyl)acetamide; M-(4-(2-(5-amino-8-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)phenyl)-4- methylbenzenesulfonamide; 3-methyl-9-p-tolyl-9,10-dihydrobenzoHPfuro(2,3-811,7|naphthyridine-6-amine; 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2 -yl)ethyl)-3-methylbenzonitrile, 4-(2-(5-amino-8-methylbenzo[1,7|inaphthyridin-2-yl)ethyl)-N-(2-aminoethyl)-3-methylbenzamide; 8-methyl-2-(2-methyl-4-(1H-tetrazol-5-ylophenethyl)benzo DP, 7|Inaphthyridin-5-amine; methyl 2-(4-(2-(5-amino-8- methylbenzo(1,7|Naphthyridin-2-yl)ethyl)-3-methylbenzamido)-4-methylpentanoate; methyl 2-(4-(2-(5-amino-8-methylbenzo|DI,7|naphthyridine-2 -yl)ethyl)-3-methylbenzamido)acetate; 2-(4-(2-(5-amino-8- methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzamido)-4- methylpentanoic acid lots; /2-(4-(2-(5-amino-8-methylbenzo ЧИ, 7|Inaftyridin-2-yl)ethyl)-3-methylbenzamido)acetic acid; /6-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)hexan-1-ol; 7-(5-amino-8-methylbenzo|D(1,7|naphthyridin-2-yl heptanoic acid; 11-(5-amino-Y-methylbenzo (Schy, 7|naphthyridin-2-ylundecan-1-ol); ethyl 2-(4-(2-(5-amino-8-methylbenzo CHY, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)acetate; 2-(4-(2-(5-amino-8- methylbenzo ЦІ1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)acetic acid; 3-methylphenoxy)propanoic acid; 6-(4-(2-(5-amino-8-methylbenzol/1,7|inaphthyridin-2-yl)ethyl)-3-methylphenoxy)caproic acid; 8-methyl-2 -(2-methyl-4-(methylthio)phenethyl)benzo CI, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(methylsulfonyl)/phenethyl)benzo| DY, 7|Inaphthyridin-5-amine ; 2-(4-(hexyloxy)phenethyl)-8- methylbenzo ХІ, 7|Naphthyridin-5-amine; 8-methyl-2-(4-phenethoxyphenethyl)benzo| DY, 7|Naphthyridin-5-amine; 8- methyl-2-(4-«(pentyloxy)phenethyl)benzo (1, 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(4-methylpentyloxy)phenethyl)benzo|C1, 7UInaphthyridin-5-amine ; 2-(2-fluorophenethyl)benzo|ЦІ1, 7ІNaphthyridin-5-amine; 2-(3-fluorophenethyl)benzoЧІ, 7|naphthyridine-5-a mine; 2-(4-fluorophenethyl)benzo|C1, YInaphthyridin-5-amine; /-2-(2-(thiophen-3-yl/ethyl/benzo|CI1, Y-naphthyridin-5-amine; (5-aminobenzosHI, 7|naphthyridin-2-yl)methanol; 2-(3,4-dimethylphenethyl) benzo CH, 7|naphthyridin-5-amine; 2-(3,4-dimethylphenethyl)-8-methylbenzo|(PCI1,7|naphthyridin-5-amine; 2-(3,5-dimethylphenethyl)-8-methylbenzo . 7|Inaphthyridin-5-amine; 2-(aminomethyl)-8-methylbenzo|C(1,7|Inaphthyridin-5-amine; M-,8-dimethylbenzo| CP, Uinaphthyridin-2,5-diamine; 2-( 5-amino-8-methylbenzo(1,7|naphthyridin-2-yl)-1-phenylethanol; 2-(5-amino-8-methylbenzo(C1,7|naphthyridin-2-yl)-1- (4 -methoxyphenyl)ethanol; 2-(biphenyl-2-yl)y-H-methylbenzo 1, 7|Inaphthyridin-5-amine; 2-(2-(2,6- dimethylpyridin-3-yl/ethyl)-8- methylbenzo CI, 7|naphthyridin-5-amine; /2-(2-(5-methoxypyridin-2-yl)ethyl)-8-methylbenzo|DI, 7|naphthyridin-5-amine; 3-(4-(2 -(5-amino-8-methylbenzo|DI1,7|naphthyridin-2-yl)ethyl)phenyl)propanoic acid; 5-(2-(5-amino-8-methylbenzo CY, 7Naphthyridin-2-yl)ethyl) -4- methylp iridin-2(1H)-one; 6-(2-(5-amino-8-methylbenzo DP, 7|Inaphtyridin-2-yl)ethyl)pyridin-3-ol; 8-methyl-2-(4-(trifluoromethoxy)phenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(2-(2,3-dihydro-1H-inden-5-yl)ethyl)-8-methylbenzo HCI, 7|Inaphthyridin-5-amine; /-2-(2-(2,3-dihydro-1H-inden-5-yl)/'ethyl)/benzo DI, 7|Inaphthyridin-5-amine; (E)-3-(4-(2-(5-amino-d-methylbenzo CHY, 7|naphthyridin-2-yl)ethyl)-3-methylphenyl)acrylic acid; (E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo CI, 7|Naphthyridin-8-yl)acrylate; (E)-8-(2-cyclopropylvinyl)-2-phenethylbenzo|C1,7U|Inaphthyridin-5-amine; 8-pentylbenzo(DI, 7|naphthyridin-5-amine; (E)-8-(2-cyclopropylvinyl/benzo CH, 7|Inaphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-phenethylbenzo|C1, 7-Naphthyridin-5-amine; (5-amino-2-phenethylbenzo|CI1, 7-Naphthyridin-8-yl)umethanol; (5-amino-2-(4-methoxy-2-methylphenethyl)benzo| DI, 7-Naphthyridin-8- yl)umethanol; 3-(2-(5- aminobenzo| 11, 7Y-Inaphthyridin-2-yl)uethylphenol; 2-(2-methoxyphenethyl)benzo|ЦІ1, 7YInaphthyridin-5-amine; 2-(4-ethylphenethyl)benzo DP , 7|Naphthyridin-5-amine; 2-(4-ethylphenethyl)-8-methylbenzo OR, 7|Naphthyridin-

B-amine; 2-(4-(dimethylamino)phenethyl)benzo|DI1,7|naphthyridin-5-amine; 2-(4-(piperidin-1-ylphenethyl)benzo|DI1,7|naphthyridine-5-amine; 2-(4-tert-butylphenethyl)-8-methylbenzo|

B-amine; 8-methyl-2-(4-(piperidin-1-yl/uphenethyl)benzo CHY, 7|naphthyridin-5-amine; 2-(4-methoxyphenethyl)-8-methylbenzo HCI, 7|naphthyridin-5-amine; 2-(3,5-dimethoxyphenethyl)-8-methylbenzo CI, 7|Inaphthyridin-5-amine; 8-methyl-2-(2-«-trifluoromethyl)phenethyl)benzo CI, 7|Inaphthyridin-5-amine; 4-(2-(5-amino-8-methylbenzo ХІ, 7|Inaftyridin-2-yl)ethyl)-M-hydroxybenzimidamide; 4-(2-(5-amino-8-methylbenzol,7|inaphthyridin-2-yl)ethyl)benzonitrile; 8-methyl-2-(4-(1-morpholinoethyl)phenethyl)benzo C(1,7|Inaphthyridin-5-amine; 2-(4-aminophenethyl)-8- methylbenzo ХІ, 7|Inaphthyridin-5-amine; 1-(4-(2-(5-amino-8-methylbenzo| 1,7UInaphthyridin-2-yl)/ethyl)phenyl)guanidine; 8-methyl-2-(4-(1-(phenethylamino)ethyl/uphenethyl) )benzo DP, 7|Naphthyridin-5-amine; 2-(4-(2-(5-amino-8-methylbenzo| SHI, 7|Naphthyridin-2-yl)ethyl)phenyl)acetonitrile; 2-(4- (piperidine-1-

ylmethyl)phenethyl)benzo OR 7|naphthyridin-5-amine; 1-(4-(2-(5-aminobenzoic acid, 7|naphthyridin-2-yl)ethyl)benzyl)piperidin-4-ol; 2-(4-(aminomethyluphenethyl)benzo|ЦІ1, 7|Inaphthyridin-5-amine; 2-(4- ((ethylamino)methyl)phenethyl)benzo|ЦІ1, 7ІInaphthyridin-5-amine; 2-(4-(2 -aminopropan-2-ylphenethyl)benzo|DI, 7|naphthyridin-5-amine; 1-(1-(4-(2-(5-aminobenzo ЧИ, 7|Inaphthyridin-2-yl)/ethyluphenyl)ethyl)pyrrolidine -3-carboxylic acid; 8-methyl-2-(4-(1- (phenylamino)ethyl)/phenethyl)benzo|D(I1, YInaphthyridin-5-amine; 2-ethyl-8-methylbenzo CI, 7Inaphthyridin-5 - amine; (5-amino-bYa-methylbenzo DP, 7|Inaphthyridin-2-yl)methanol; 8-methyl-2-propylbenzoShP, 7|Inaphthyridin-

B-amine; 2-(2-(1H-indol-5-yl)ethyl)-8-methylbenzo| CI, 7|naphthyridine-5-amine; 2-(4-ethoxyphenethyl)-8- methylbenzo ХІ1,7|Inaphthyridin-5-amine; 8-methyl-2-(4-phenoxyphenethyl)benzo or 7|naphthyridin-5-amine; 2-(2,4-dimethylphenethyl)benzo CI, 7|Inaphthyridin-5-amine; 2-(2,4-dimethylphenethyl)-8-methylbenzo Х/1,7|Inaphthyridin-5-amine;. 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo CH, 7|naphthyridine-

B-amine; 4-(2-(5-amino-8-methylbenzopyridine, 7-inaphthyridin-2-yl)ethyl)-3-methylphenol; 2-(2-(2,3- dihydrobenzofuran-5-yl)ethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine; 2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethanol; 3-methyl-9-phenyl-9,10-dihydrobenzo|Pfuro|2,3-

BI, 7|Inaphthyridin-6-amine; 8-methylbenzo DI, 7|naphthyridine-2,5-diamine; 1-(5-amino-8-methylbenzo H1,7|Inaphthyridin-2-yl)upropan-2-ol; 2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)acetonitrile; M-(5-amino-d8-methylbenzo|11,7|naphthyridin-2-yl)acetamide; 2-(5-amino-8-methylbenzo CII1,7|Inaphthyridin-2-yl)-1-(2,4-dimethylphenyl)ethanol; 2-(2-(6-methoxy-4-methylpyridin-3-yl)ethyl)-8-methylbenzo| DY, 7-Inaphthyridin-5-amine; 4-(4-(2-(5-amino-β8-methylbenzo DP, 7|Inaphthyridin-2-yl)/ethyl)phenyl)butan-1-ol; methyl 3-(4-(2-(5-amino-8-methylbenzo|DY, 7|naphthyridin-2-yl)/ethyluphenyl)upropanoate; 3-(4-(2-(5-amino-1-methylbenzo|DY) , 7|Naphthyridin-2-yl)ethyl)phenyl)propan-1-ol; 4-(4-(2-(5-amino-1-methylbenzol) -2-ol; 2-(4-(aminomethyl)phenethyl)-8-methylbenzo DP, 7|Inaphthyridin-5-amine; (E)-ethyl 3-(4-(2-(5-amino-8- methylbenzo ZHI/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate; ethyl 3-(4-(2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethyl) -3-methylphenyl)propanoate; 2-(4-(2-(5-amino-8- methylbenzo C1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzyl)propane-1,3-diol; 3- (4-(2-(5-amino-8-methylbenzol/1,7|inaphthyridin-2-yl)ethyl)-3-methylphenylpropanoic acid; 5-amino-2-(4-methoxy-2-methylphenethyl)benzo |D(I1,7Inaphthyridin-8-carbaldehyde; ethyl 4-(2-(5-amino-8-methylbenzoSHII1,7|Inaphthyridin-2-yl)ethyl)benzoate; 8-methyl-2-(4-methylphenethyl)benzo |D/I1,7Inaphthyridin-5-amine; 2-(4-(2-(5-amino-8-methylbenzo| (1,7UInaphthyridin-2-yl)ethyl)phenyl)propan-2-ol; (4- (2-(5-amino-8-methylbenzo DY, 7UInaft iridin-2-yl)ethylphenyl)methanol; ethyl 4-(2-(5-amino-8-methylbenzo CI, 7-Inaphthyridin-2-yl)ethyl)-3-methylbenzoate; 4-(2-(5-amino-8-methylbenzo C1,7|Inaphthyridin-2-yl)ethyl)-3-methylbenzoic acid; (4-(2-(5-amino-8-methylbenzo 1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)methanol; 8-methyl-2-(2,4,6- trimethylphenethyl) benzo CHY, 7|Inaphthyridin-5-amine; /2-(4-(2-(5-amino-8H-methylbenzo CI, 7-Naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol; 8-methyl-2-(4-propoxyphenethyl)benzo DY, 7|naphthyridin-5-amine; (E)-3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo DP, 7|Inaphtyridin-8-yl)acrylic acid; ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|ЦЙ1, YInaphthyridin-8-ylpropanoate; 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo|ДЙ1 . |Inaphthyridin-8-ol; /-5-aminobenzo| CI, 7UInaphthyridin-8-carbaldehyde; 1-(5-aminobenzo SHI, 7|Inaphthyridin-8-yl)ethanol; - 1-(5- aminobenzo| CI, 7UInaphthyridine -8-yl)ethanone; 8-isopropylbenzo (DI, 7|naphthyridin-5-amine; 8-vinylbenzo DP, 7Inaphtyridin-5-amine; 8-ethylbenzo| CHY, 7|naphthyridin-5-amine; 8- (methoxymethyl )benzo|D/I1, 7Naphthyridin-5-amine; (5-amino-2-(4-methoxyphenethyl)benzo SCh, 7|naphthyridin-8-yl)methanol; benzoSCh, "I naphthyridine-5,8-diamine; 8- (aminomethyl)benzo CI, 7|Naphthyridin-5-amine;. 3-fluoro-8-methylbenzo (1,7 |Naphthyridin-5-amine; (5-amino-

3-fluorobenzoic acid, 7-naphthyridin-8-yl)methanol; Z-chlorobenzo SHI, 7-Naphthyridine-5,8-diamine; 3-fluorobenzoic acid, 7|Inaphthyridine-5,8-diamine; 8-isobutylbenzo|DY1,7|naphthyridine-5-amine; (E)-8-(prop-1-enyl)benzo SH, 7|naphthyridin-5-amine; 8-propylbenzo CHIP, 7|Inaphthyridin-5-amine; 8-(2- cyclopropylethyl)benzo|(ЦІ1, Yanaftyridin-5-amine; 8-phenethylbenzo DI, 7|naphthyridin-5-amine; (5-amino- 2-(4-bromophenethyl)benzo DP, 7|Inafthyridin- 8-yl)methanol; 2-(4-methoxy-2-methylphenethyl)-8-pentylbenzo|DY, 7|naphthyridin-5-amine; 8-(2-cyclopropylethyl)-2-(4-methoxy-2-methylphenethyl) )benzo|D/Y1, 7Inaphthyridin-5-amine; (5-amino-2-(2,4,6-trimethylphenethyl)benzo CHY, 7|Inaphthyridin-8-yl)methanol; (5-amino-2-( 4-propoxyphenethyl)benzo ХІ, 7-Naphthyridin-8-yl)methanol; (2-(2-(1H-indol-5-yl)ethyl)-5- aminobenzo| CI, 7UInaphthyridin-8-yl)methanol; methyl 4-(2 -(5-amino-8-methylbenzo|(DI1,7|naphthyridin-2-yl)ethyl)-3-methylbenzoate; 4-(2-(5-amino-8-methylbenzo (1, 7|Inaphthyridin-2- yl)ethyl)-N,3-dimethylbenzamide; 4-(2-(5-amino-Y-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M,

C-dimethylbenzamide; 2-(4-Methoxyphenethyl)benzo|(DI1,7|naphthyridin-5-amine; 2-(4-methoxy-2-methylphenethyl)benzo|D/I1,7Inaphthyridin-5-amine; 4-(2-(5 -amino-d-methylbenzo|SHI, 7Inaphthyridin-2-yl)ethyl)-3-methylbenzamide; 4-(2-(5-amino-b8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-M, M, 3-

trimethylbenzamide; 4-(2-(5-amino-8-methylbenzo DC, 7-Naphthyridin-2-yl)ethyl)-M-(2-hydroxyethyl)-3-methylbenzamide; 4-(2-(5-amino-8-methylbenzo[D/I1,7-Naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-3-methylbenzamide; /(4-(2-(5-amino-3-methylbenzo DY, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)(pyrrolidin-1-yl)umethanone; 4-(2-(5-amino-8-methylbenzo (1,7 |naphthyridin-2-yl)ethyl)-M-(2-(diethylamino)ethyl)-3-methylbenzamide; (4-(2-(5 -amino-8-methylbenzo 1, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazin-1-yl)umethanone; (4-(2-(5-amino-8-methylbenzo| 1 . methyl-

M-(2-(pyrrolidin-1-yl)ethyl)benzamide; 4-(2-(5-aminobenzo|(DI1,7|naphthyridin-2-yl)ethyl)-M-(2-(dimethylamino)ethyl)-M, 3-dimethylbenzamide; 4-(2-(5-amino -I-methylbenzo DY, 7|naphthyridin-2-yl)ethyl)-

M-(2-(dimethylamino)ethyl)-M-methylbenzamide; 2-(4-(2-(5-aminobenzo|D|I1,7UInaphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol;. 2-(4-butoxyphenethyl)-8-methylbenzo DI, 7-Naphthyridin-5-amine; 2-(2-(biphenyl-4-yl)ethyl)-8-methylbenzo|(DCI1,7|naphthyridin-5-amine; 2-(1,3-dihydroisobenzofuran-1-yl)methyl)-8-methylbenzo , 7|Inaphthyridin-5-amine; 8-methyl-2-(4-(2-methylallyloxy)phenethyl)benzo|D(1,7|naphthyridin-5-amine; 2-(4-(isopentyloxy)phenethyl)-8- methylbenzo SHІ, 7|Inaphthyridin- 5-amine; 4-(2-(5-amino-8-methylbenzo DY, 7Inaphthyridin-2-yl)ethyluphenyl propyl carbonate; ethyl 5-(4-(2-(5-amino-8-methylbenzo|D(І1 ,7|Naphthyridin-2-yl/uethylphenoxy)pentanoate; 2-(4-(Cyclopentyloxy)phenethyl)-8-methylbenzo CI, 7Naphthyridin-5-amine; 2-(4-(Cyclobutylmethoxy)phenethyl)-8-methylbenzo| (1, 7Inaphthyridin-5-amine; 8-methyl-2-(4-(2- morpholinoethoxy)phenethyl)benzo|DI, 7|Inaphthyridin-5-amine; 2-(4-(2-(5-amino- 8-methylbenzo ХІ1,7|Inaphthyridin-2-yl)ethyluphenoxy)-1-phenylethanone; 5-(4-(2-(5-amino-8- methylbenzo ХІ1,7|Inaphthyridin-2-yl)uethylphenoxy)pentanoic acid 2-(4-(2-(5-amino-8-methylbenzo ЩХ1,7|Inaftyridin-2-yl)uethylphenoxy)ethanol; 2-(4-(2-(5-amino-8-methylbenzo Щ/1) ,7|Inaphthyridin-2-ylluethylphenoxy)-M,M-dimethylacetamide; 8-methyl-2-(2-methyl-4-(2-morpholinoethoxy)phenethyl)benzo|DI, 7|Inaphthyridin-5-amine; 2- (2-(4-(2-(5-amino-8-methylbenzol/1,7|inaphthyridin-2-yl)ethyl)-3-m ethylphenoxy)ethoxy)ethanol; diethyl 3-(4-(2-(5-amino-8-methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate; 3-(4-(2-(5-amino-8-methylbenzo H/1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonic acid; 2-(4-butoxy-2-methylphenethyl)-8-methylbenzo DCP, 7-Naphthyridin-5-amine; 2-(4-(2-(5-aminobenzo|DI1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 2-(2-(4-(2-(5-aminobenzo|DI1,7Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethanol; ethyl o //5-(4-(2-(5-amino-8-methylbenzo|S/1,7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate; 5-(4-(2-(5-amino-8-methylbenzo|SHI, 7|naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoic acid; 2-(4-(2-(5-amino-8-methylbenzo C(1,7|Inaphthyridin-2-yl)ethyl)-3-methylphenoxy)ethanol; 4-(2-(5-amino-1-methylbenzo DY, 7|Naphthyridin-2-ylethyluphenyl ethyl carbonate; methyl 4-(4-(2-(5-amino-Y-methylbenzo DP, 7|Naphthyridin-2-yl)ethyluphenoxy)butanoate; 4-(4-(2 -(5-amino-8- methylbenzo ЧИ, 7|naphthyridin-2-yl)ethylufenoxy)butyric acid; 4-(4-(2-(5-amino-8- methylbenzo Х/1,7|Inaphthyridin-2- yl)ethyl)-3-methylphenoxy)butyric acid; 2-(4-(isopentyloxy)-2-methylphenethyl)-8-methylbenzo DCP, 7|Inaphthyridin-5-amine; 4-(2-(5-amino- 8-methylbenzo|D/I1, 7|Inaphthyridin-2-yl)ethyl)phenyl hexyl carbonate; 2-(2,4,6-trimethylphenethyl)benzo|DI, 7|Inaphthyridin-5-amine; (5-amino-2- (2,4-dimethylphenethyl)benzo DP, 7|Inaphthyridin-8-yl)methanol; diethyl 3-(2-(4-(2-(5-amino-8- methylbenzo) /1,7|Inaphthyridin-2- yl)ethyl)-3-methylphenoxy)ethoxy)propylphosphonate; diethyl 3-(2-(2-(4-(2- (5-amino-8-methylbenzo| DI, 7|Inaphthyridin-2-yl)ethyl)- 3-methylphenoxy)ethoxy)ethoxy)propylphosphonate; 4-(2-(5-amino-8-methylbenzo DP, 7Inaphthyridin-2-yl)ethyl)-3-methylphenyl d Imethylsulfamate; (5-amino-2-(4-(dimethylamino)phenethyl)benzo CHY, 7|naphthyridin-8-yl)methanol; 2-(4-(Dimethylamino)phenethyl)-8- methylbenzo SHHI, 7|Inaphthyridin-5-amine; /4-(2-(5-amino-1-methylbenzo H(1,7|Inaphthyridin-2-yl)ethyl)uphenol; 1-(4-(2-(5-amino-8-methylbenzo|D/1) ,7|naphthyridin-2-yl)ethyl)phenyl)ethanone; 2-(4- ((dimethylamino)methyl)phenethyl)-8-methylbenzo| 1,7UInaphthyridin-5-amine; 2-(4-(1- ( dimethylamino)ethylphenethyl)-8-methylbenzo|DI1,7|naphthyridin-5-amine; 1-(4-(2-(5-amino-8- methylbenzoSHII1,7|Inaphthyridin-2-yl)ethyl)phenyl)ethanone oxime ; 8-methyl-2-(4- ((methylamino)methyl)phenethyl)benzo|(DI1,7|naphthyridin-5-amine; (4-(2-(5-amino-8- methylbenzoSHI1,7|Inaphthyridine- 2-yl)ethyl)benzylamino)ethanol; 8-methyl-2-(4-(pyrrolidin-1-ylmethyl)phenethyl)benzo OR 7|naphthyridin-5-amine; 2-(3,4-dimethoxyphenethyl)-8- methylbenzo SHRI, 7|Inaphthyridin-5-amine; 2-(1-(4-(2-(5-amino-8-methylbenzoShRI), 7|Inaphthyridin-2-yl)ethyl)uphenyl)ethylamino)ethanol; 1-( 4-(2-(5-amino-8-methylbenzo DP, 7Naphthyridin-2-yl)/ethyluphenyl)ethanol; 8-methyl-2-(4-(oxazol-5-ylopheneethyl)benzo DP, 7|naphthyridine-5 -amine; 3-(1-(4-(2-(5-amino-8-methylbenzo|DY, 7|Inaphthyridin-2-yl)ethyluphenyl)ethylamino)propanenitrile; / (2К)-2-(1-( 4-(2-(5-amino-8- methylbenzo CI, 7|Inaphthyridin-2-yl)ethyl)phenyl)ethylamino)propan-1-ol; 8-methyl-2-(4-(1-(piperazin-1-yl)oethylufenethyl)benzo DP, 7|Inaphthyridin-5-amine; ((25)-1-(1-(4-(2-(5 -amino-8-methylbenzo CH, 7|naphthyridin-2-yl)ethylphenyl)ethyl)pyrrolidin-2-ylmethanol; M'-(1-(4-(2-(5-amino-8-methylbenzo) Х/1 7|Naphthyridin-2-yl)ethyluphenyl)ethyl)-M2,M2-dimethylethane-1 2-diamine; 3-(1-(4-(2-(5-amino-8-methylbenzo| SHI), 7|naphthyridine- 2-yl)ethyluphenyl)ethylamino)upropanoic acid; 8-methyl-2-(4-(1-(4- methylpiperazin-1-yl)uethyluphenethyl)benzo DP, 7|Inaphthyridin-5-amine; M2-(1- (4-(2-(5-amino-8-methylbenzol/1,7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)-M',M'-dimethylpropane-1 2-diamine; 8-methyl-2- (4-(1-

(2-(pyridin-4-yl)uethylamino)dethyluphenethyl)benzo DP, 7|Inaphthyridin-5-amine; M1-(1-(4-(2-(5-amino-8-methylbenzo|C1,7|Inaphthyridin-2-yl)ethyl)phenyl)ethyl)-Me, Me-diethylethane-1 2-diamine;. 2-(4-(Dimethylamino)-2-methylphenethyl)-8-methylbenzo DI, 7-Naphthyridin-5-amine; 1-(1-(4-(2-(5-amino-8- methylbenzo Х/1,7|Inaphthyridin-2-yl)ethyluphenyl)ethyl)pyrrolidine-3-carboxylic acid; 4-(1-(4- (2-(5-amino-8-methylbenzo| SHI, 7|naphthyridin-2-yl)ethyl)phenyl)ethylamino)phenol; 1-(1-(4-(2-(5-amino-8-methylbenzo) SHI) .

By way of example only, the compound benzoic acid 1,7-inaphthyridin-5-amine (Example 1) has ECs of 2100 μM, 14 μM, and 0.84 μM in NEK293-TI 87, NEK293-TI K8, and I-6 YANRVMS studies, respectively.

By way of example only, the compound 8-methylbenzo CY, 7-Naphthyridin-5-amine (Example 5) has ECs of 15.8 µM, 9.01 µM and 0.396 µM in NEK293-TI 87, NEK293-TI K8 and 1-6 YARVMS studies, in accordance.

By way of example only, the compound 8-fluorobenzoic acid, 7|Inaphthyridin-5-amine (Example 14) has ECs of 37 μM and 6.38 μM in NEK293-TI K8 and II-6 YANRVMS studies, respectively.

Just as an example, the compound 5-aminobenzo (1,7 |naphthyridin-3Z(4H)-one (example 15) has an ESvo of 241

MKM in NEK293-TI K7 studies.

Just as an example, the compound 2-ethylbenzo DY, 7|naphthyridin-5-amine (Example 30) has ECs of 8.64 µM, 13 µM and 2.28 µM in NEK293-TI 87, NEK293-TI K8 and II-6 YANRVMS studies, in accordance.

Just as an example, the compound 2-phenethylbenzo H/1,7|Inaphthyridin-5-amine (Example 33) has an ESvo of 2.44

MKM and 2.28 μM in NEK293-TI K7 and I--6 YANRVMS studies.

By way of example only, ECs for TI K-7 stimulation by certain other compounds of Formula (I) are presented in Table 2 below. The ID number for each compound is the number of the Example above that describes its synthesis.

Table 2

Mo (NM)

By way of example only, ECs for TI K-8 stimulation by certain other compounds of Formula (I) are presented in Table C below. The ID number for each compound is the number of the Example above that describes its synthesis.

Table C

Mo (MKM) at 11111161

It is understood that the examples and embodiments disclosed in this description are presented for illustrative purposes only, and that various modifications or changes thereof will be suggested to those skilled in the art, and are included in the spirit and content of this application and the scope of the attached Formula . All publications, patents and patent applications cited in this specification are hereby incorporated by reference for all purposes.

LIST OF SEQUENCES

"1105" IVMII S

Sope?, AIeh "120" COMPOUNDS AND COMPOSITIONS AS MODULATORS OF THI A ACTIVITY "130" R1I32b6RS20 -160" 6 "170" Raiepiip megsiop 3.5 "21051 "211" 248 "212" RAT "213" Meibzepa tepipoyidev5 "400" 1 ua! i Aizh Aia der tie b1iu AtTa biu besh ATa Ar ATa tsets tTng o Ala vgo 1 5 | Kk) 15 bec dr Ni uz ABrogu5 STU Sveu bip bag oieu TVgoiets A5r o sty bek 2 255 30

Wow! Aga tsu ABp biv vuh sen o guh cen action ATa siy s1u ATa si rub o 45

Tpg otu biu ABp o s1u Ar ob5eg without dey Tpg obiu dSu5 Geu vu5 Ap o OR 50 yuub5 Ua! 5eg Aga rRpe Ar RNe tiv Aga bip te bish Ua! Abrosiu sei 65 70 75 5o

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Gets ar ni 1u5 Ar vu ego ben oip ego yeny tt oseu Azrosip 5eg 23 25 30

Uuaii AgYa uz ap ot uv ze uz gay Aia Aa bij 01uU AtTa bish vu

Tys tTug biu A5p o biu Ar 5eg iv Ai tig o biu uz gay gub Ap AZr 60

Guye ma! beg Aha RNe A5r Re iTe Ago sii Tie bi mai A5r o1u vp 65 70 75 vo

Mei tb tTigoieno obi 5eg biu 61 ve bij i1e tugo vuye b1p Ar niv 85 90 25 bek dia Ua! mai Aia ve biy 112. biy buye Ite ABY ABY RgO OR Su 100 105 110

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180 185 190

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In the zoo

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ssh nih ser bukh tik sei beach b1l Aza muai si ey ATa ATa Aa b 180 185 90

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A1a vkho ma! Uai bek bis uz 1) tpm obi ATa bu5 bis A5r AIa vgo sii ATa siu begobipobiu bip s1u Aa Rso 5ego Aia biu biu s1u siy 34 der mes Aia Aa Ua! ches bii bi Ap tab ostTu Azp o siu S1u Aia Aa 50 55 bo

Aia tik A5rogu5 rRgOo Bu Ayap ish A5r ot: bu AЯa bip Aa AZr mes 65 70 75 o

Rgo beep dp ATa Aia AYU YES oAzrobeg re tig Rgo Ap oniV TIg RGO 855 90 95

AtTa ek dey Mei rgo dia biu dep Meb 10 Ap bij ATa Rgo ar Aia 160 105 po s1u bi 5egobiu bip Rgo Aa Azpobip Rgo Ar Mee ATa A5potag Aa 115 120 195

Azr'aiu Mei bij STU A5r Abo rogo bek ATa biu bi bij dep ATa s1U 130 135 140 dai tAgoAia Aia siya b1u tve dp bij ATa bib ABZA Ai ap tvps Aia 145 150 155 160 stu zeg bip A5p Rgo Aida 5eg bek TT ABY RGO 5eg Aa TVR o Abpobog 165 170 175 in b1u AbroRpe SiuU Ago tigoAZp ma! STU Ap bek omai Wow! 116 Or io 155 159 s1u Rgo 5eg 01" d5p o i1e tvgosets o tvee Nib buh sub biu Ar 5eg suh 195 200 205 i zeg biu Ap Ai Re se Abo obi siv Uai siy yeu guye 5Zebobim rve 210 215 more

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RgO tab ob5eg vna Aia Ag pe dgu Ago 5eg Aid Agu ego Abo aka Bas 75 280 285 mesh go ATa bid Mes Rgo Sed 112 Rgo ma! Abzp bip ATa Ar o tig o vets 2930 295 300

Ii mai A5r bu bij dia ma! bek gen tnig s1u No beg stu Ap otiv 305 | 310 315 329

Re Aia rgo sit a1Uu dep tugo OR Tub without TAig o Tuk sim Aia oi Gu 325 330 135 tseu RgOo siu siu 5eg tuye dia iets dru ma! beep otu biv Rgo Bek was for 345 150 s1u bi Mes ce Aa siu tb oAia mai tugo dep STU bish ma! hetsnia 355 from 3655

Rpe niya Te BI Aba s1uU AKo RRO Zeg o Rgo 5egodga b1u Aga RBe Aa. 370 375 volumes

Aia tzus ua! Ar Riv Si Zeg zu bek oua! ABrobiuU I116 i16 Ar ozeg 385 390 3985. adOo otu Azr o biu bech ni mebt biu tieobiy buye vNe Bu Av Aid i1e der 405 ATO | 435 biUu dzp obiu Ra i uye 61u TbgotTgrotve bib Ap os1u si biu Arma 420 425 30 zak sim sub ryv tuye Ye1u Rgo Aida b1u 16 bin hai Aia S1Uu uz here 435 40 445 zeg tug Aga Rgo Tig Ar ATa ssh Su5 biu biu Rpe siu Uai Re dia 450 455 or s1u uz im5 bij bij Abzrosiu b5eg siu e1u biu SIM ATa tng tugo gu 4655 470 475 | A8O0

Uai der oi Tut niz Aza A5p ATa Ako Ra ATa tiv Abr mi RNE ABZ 485 Acho | 495

Tygobeg Teg o dyap Whoa! biu sbiu RNe tour b1iu ep tb o 0Ttu beb hudi s1o 500 595 510

RIV A5r o bip Aia tsu Ago Ar osF1u buh t1e Azr yt1e tv yTa Rgo ma 515 520. 525

Aia dep o bec bip bZeb o biu zek bip no Re tTig oder niv gay su 5eg 530 535 540

ATa A5r o ITE Re AZroATYA ATa o10 Tug Rgo A5r otie Ago RBe ma! 5eg 545 z50 Z5U 560

Te Sub re dep rNe dep biu iu5 uz ieyp Uai beg udi der oh dvy 555 5620 Z75 em Tit met ni su buh tVg o Aia vgo Uai gub svi Bu5 ATa ob bu 580 585 ZO

Re AB oSuye tugo siy beb o Rgo mes ATa suya tpg Osiy ma! Suh s1u siyu 595 bo 505 der Re 5eg o tvg here even Azrodgo Tk gu terobiu ma! Ar Tug Bei vii 615 620

Wow two Wow! oiu mes tb o Buz 5egouai Ak te Ar t1e bij yiv Su 525 vo 6535 640

Aa1a Aza uh siy "2105 5 "-2115 434 "2125" RAT "213" Meib5zegia tepipodyaiv "4005" 5 mes mai bek dia ma1! iiiye b0iu bek dia dia mai siu A1i3 tsuz bek Aid 1 5 10 15

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Gen Se bep ces b1iu siy ma! ATa tk obi biu bii Su bip RNe ha 55 70 75 vo soTu bip ti ATa dga bek o oish siy Aid dia sto sbiu maii Tu A5p otu 85 90 95 tiee tpe mai Aid zeg osei rgo Ago Tg ATa b1iu AZr ti ATa bi der 100 105 110

Te Ter ABY TVgobeg obu mai Ag Aia tik bez be) b1u Te bek RgO і15 122 125

Aia tYagobipy ATa Ag uai bu Tiye Ua! tb otug biu A5p o Udy tvg tuye 130 1325 140 mai mee s1u I16 mesh tak RgO her bish bip Aia sp i1e tvg so1y Bu 145 150 155 160 uai bek Tne tik ouai siu ma! Sip was ma! her tyg ogets tui S1ya ABy 165 170 175 tug Ua! bij ag stu 5egooiu biu siu stu Uai Aid ATa Ar T1e stu 180 185 130 dia sotu hy Aia Ar ATa gen TK o Aia Rgo Gay Ar Ni Gu OR Guz 195 200 705 sIu ev biy beg o zen tlo sei or biy beg ma! Ago yu5 lap sitz Guz 210 215 220 this vuye iven AzasAid bi B1My ATa biy uh tvg tuye b1u dp su Ar 225 0 235 240 begobvy Ayay TNg obi wuz ey was Ap AV Guz Ua! bZeg Ago Re ABr 2435 | 250 | 238 ne tITE Aku bij i11e bij mai A5robim bij Ge ti TK o Seu oi bag 260 265 270 stu ish vne sii Ua! tugo vu bipobeg niv 5eg action fec tr ATa vve 275 280 285 bip tng axis bij t1Te Siv Abrobag bij Ni beg bi Gu5 Mei Uai ATa 290 295 300 uz Aga bifull aku i1e biu A5r o ti1e data biu sib niz Tig bek RNe 305 310 315 320

Ar buz ce RgOo siu b1u STU Ago ATa TR otuye dra biu tb ATa RNe 325 | 330 335 biu zag dr dr Aa siu O1u uz iets tvs Tut tNe 116 Azr o RNa dia 340 345 350

Aiv Sub soi siu A5y b1u gruz IІe bij ni Sei bukh b5eg o Rgo bi geo 355 360 365

AzpoUa! AZOo yen Aia ATa ATa ABroIIv bue Rgo ABrob1u bue5 Aka niv 370 375 350 dia ud! 112 bek biu 5eg mai Se Tu Azy bip ATa sti buh stu bag 385 390 385 400 tugo zag cen Yeiu she ve s1u b1u Gu«sA1a bip sin Udi ATa b1u 5es 495 po 415

AiTa bii Ua? buz tTNgomai A5p otu tie Aga ni tiv siu ge AiTa Aid 420 Sya 430 ru ap -2105" 6 "2115" 327 "2125" RAT "213" Meib5zegia tepipodyaiv "400" 6

Aia Tk oAbp Advr dar Ar ma! uh su ATa ATa tak mai ATa 16 ATa i 5 10 15

Aia Aa tight A5p AZp o b1iu 1 bi 112 Or b1iu Rpe uh Aia Tu sy 20 25 zo tTiRolTe Tut AZr t16 Ar siy Azrobim ts I1e TB otzus suz Ar Aa tТг Aiz Aia Azo ud! biz dia der dr RNe Gu biu iets biu vy g uv 5E | because wow! mai tTyg o dby rez tvgoiuv tk Oma! Azy bio AB vm bi Ap 65 7a 75 vo

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85 out of 95

Tyg gub bech AIa OR Tyg Ar Aa ATa sey Aia Avrotpg Ar o ATa Aa 100 105 110 cen Ar ATa Tak o tTig OA АЙТya vu ABp Su ev b1uU biv Ap o і18 tTvg 115 120 125

TNe vve Aia biv biv tTvgogsukh Tr ody ti1e Ua! (uz che Azr o bis I uz 130 135 140 ren si Aza wai did Art tik Ua! Ar ovu5 Ni Aza sim dTa Re Azp 145 150 155 160

Arota Aia der o zeg iv AzroEeiiB TVg ABY TAK iu5 Aa d5robvin Aia 165 170 175

Ua1i gu TNg oATa AzpobiSh ATa Guz bib tab oATa biv bi) Te uz bip 180 155 190

Ap Ma! Ar Aia uv mai vukh ATa Aia pizza tik Aia ATa s1u uv ATa 195 290 205 bish ATa Ata ATa siu Tpg ATa Aby tAgoATa ATa dr vu ATa S1ts ATa 21 215 a mai Ai4 Aia su mai te Abo iTiee uh ATa Ar i11e Aa Tvg o dkpokuh 225 238 235 240 der Av tiv ATa uz uh Aid Ap obeg Aa Azroua! tuye ts Ago so 245 250 255 si zeg Ar chego vuh Ne uUai Aga I112e Azov siug ge ab Aa tyk Ootick 250 265 270 bi uz Bey dr o Tig Agu bey Aia zag ATa biv Sub 5eg yiv AiTa ABr 275 Ko 285 ni d5rotpK AgYa meu Aza obiu se AZr oyi uz Tig oUdi Zeg dr hey Ago 290 va z00 iu5 bid tb de ota biu gez AtTa biv biv Aa Aa be 5eg o biU re 305 10 315 32o0

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