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    • 专利摘要:
    heteroaromatic compounds as bruton tyrosine kinase (btk) inhibitors the present invention encompasses compounds of formula (i) wherein the groups a, cy, xi and y are defined herein which are suitable for the treatment of a disease chosen from rheumatoid arthritis, systemic lupus erythematosus, scleroderma, asthma, allergic rhinitis, allergic eczema, b-cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and ankleitis .
    公开号:BR112015002590A2
    申请号:R112015002590
    申请日:2013-08-08
    公开日:2019-08-06
    发明作者:Kay Berry Angela；Mao Can；Todd Disalvo Darren；Soleymanzadeh Fariba；Martin Bentzien Joerg；Courtney Horan Joshua；Jason Burke Michael；M Zindell Renee；Liang Shuang；Bosanac Todd；Mao Wang；Shen Yue
    申请人:Boehringer Ingelheim Int；
    IPC主号:
    专利说明:

    Descriptive Report of the Patent for HETEROAROMATIC COMPOUNDS AS THRESHOLD INHIBITORS · IN BRUTON KINASE (ΒΤΚΓ
    ORDER DATA [001] This claim claims benefit to US provisional order no. serial 61 / 681,684 deposited on August 10, 2012.
    BACKGROUND OF THE INVENTION
    TECHNICAL FIELD [002] The present invention relates to new compounds that inhibit BTK and its use as medicines.
    BACKGROUND INFORMATION [003] Members of the human enzyme protein kinase family play important regulatory roles in a multitude of distinct signal transduction processes due to their post-translational modification of specific proteins through the addition of a phosphate group (Hunter, Cell , 1987 50, 823-829). Bruton's tyrosine kinase (8TK) is a member of the Tec family and plays a critical role in B cell development, activation and antibody production.
    [004] BTK's contribution to B cell biology is exemplified in the immunodeficiency of X-linked agammaglobulinemia (XLA) in humans (reviewed in Lívvall, Immunol Rev 2005, 203, 200-215 which displays attenuated calcium signaling in impairment of BCR, needs mature B cells in the periphery due to blockage between the pro- and pre-B cell stages and has lower levels of circulating antibodies than normal healthy individuals The result of recent clinical experiments with B cell depleting anti molecules -CD20 in diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) support the hypothesis that B cells offer an important mode of intervention to control au disorders
    2/118 toímunes (Townsend et at 2010). As such, the attenuation of B cell proliferation and activation through BTK inhibition calls for offering similar therapeutic benefit and is consistent with the demonstrated resistance of BTK-deficient mice to collagen-induced arthritis (Jansson, 1993, Clin Exp Immunol 94, 459-xxx) and experimental autoimmune encephalitis (Svensson et al. 2002 and Manqla et al 2004). Similarly, the clinical efficacy observed with a BlyS cell stimulating factor neutralizing body supports a role for B cells in the pathophysiology of systemic lupus erythematosus (SLE) (La Cava 2010). Given the need for BTK to produce autoantibodies, including anti-DNA antibodies, in murine SLE models (Steinberg et al 1982; Golding et al, 1983; Scribner et al., 1987; Seldin et al., 1987; Satterthwaíte et al, 1998; Takeshita et al., 1998; Whyburn et. Ah, 2003), BTK inhibitors may offer therapeutic benefit to patients with SLE.
    [005] Within myeloid cells, BTK signal transduction is necessary for the stimulated release of inflammatory cytokines such as TNF from stimulated monocytes (Norwood, J Exp Med, 10 2003, 1603-xxx) and for the cytoskeletal organization of ideal actin and lacunar bone resorption in isolated osteoclasts (Danks, 2011, J Bone and Mineral Research, 26, 182-192). Mast cells derived from bone marrow requiring BTK exhibit degranulation induced by impaired activation and release of cytokine (ref). Given the role of BTK in signal transduction processes across multiple cell types implicated in the pathogenesis of autoimmune disorders and allergic disorders, inhibition of BTK activity can provide clinical benefit in diseases such as RA, MS, SLE, asthma and disorders allergic.
    SUMMARY OF THE INVENTION [006] The invention comprises a new class of compounds
    3/118 heteroaromatics and methods to prepare and use them. These compounds are useful for the treatment of autoimmune and allergic disorders due to the fact that they exhibit good inhibitory effect on BTK.
    DETAILED DESCRIPTION OF THE INVENTION [007] In a first generic embodiment, a compound of formula (I) is provided
    Y CO [008] Ring A is:
    [009] R 1 is N (R 3 ) 2 or hydrogen;
    [0010] Cy is aryl or heteroaryl each of which is replaced by R 2 θ optionally substituted by halogen, halo alkyl, alkyl and alkoxy;
    [0011} R 2 is chosen from:
    [0012] L-Ar, alkyl and Ο μ6 alkoxy, each Ar, alkyl and alkoxy is optionally substituted by halogen, halo C M alkyl, C M alkyl, R 3 -S (O) m -, -CN, -C ( O) -N (R 3 ) 2 or alkoxy;
    [0013] L is a Hgador chosen from a bond, O,> C (O), (CHA-, -O-fCHzV-, -N (R 3 ) -, “N (R 3 ) - (CH 2 ) n -, - (CH 2 ) n -N (R 3 ) -, -C (O) N (R 3 E -C (O) -N (R 3 ) - (CH2) n “, 44 (R 3 ) -C (O) -N (R 3 ) -, -N (R 3 ) -C (O) -, -S (O) m N (R 3 ) - and -N (R 3 ) -S (O ) m -, where -CH 2 - in each L can have 1-2 hydro
    4/118 geniuses substituted by Ο ^ 3 akyla, said akyla groups can optionally divide to form a C 3 ^cloalkyl ring;
    [0014] Air is carbocide, heterodilyl or heteroaryl;
    [0015] X 1 is a linker chosen from a bond, - (CH 2 ) n -;
    [0016] Y is chosen from C r C 10 spirocide optionally containing 0-1 nitrogen atom in the ring, a nitrogen containing mono- or bicyclic heterocycle, carbocide, aryl, each replaced by an R 4 ;
    [0017] R 4 is
    it may not be hydrogen,
    5/118 [0018] each n is independently 1 -4;
    [0019] each m is independently 0-2;
    [0020] each R 3 is independently chosen from hydrogen or Cm alkyl;
    [0021] each R 5 is independently chosen from hydrogen, C M alkyl, Cm alkoxy, C- | _ 4 alkyl C-M alkoxy, [0022] - (ÇH 2 ) n -heterocycle and heterocycle each hsterocycle optionally substituted by halogen, OH and R 3 -S (O) m -;
    [0023] each group defined above for Cy, R ^ -R 5 , X-ι and Y can be where possible partially or completely halogenated;
    [0024] or a pharmaceutically acceptable salt thereof.
    [0025] In another embodiment, a compound of formula (I) is provided according to the embodiment here above and where [0026] Ring A is:
    O
    [0027] or a pharmaceutically acceptable salt thereof.
    [0028] In another embodiment, a compound of the formula (I) is provided according to any of the modalities previously mentioned and in which [0029] Cy is phenyl, pyridinyl, pyridanyl, pyrimidinyl or pyrazinyl each of which is replaced by R 2 optionally substituted by F, Cl or Cm alkoxy;
    [0030] R 2 is chosen from:
    [0031] L-Ar and Ci. 3 alkoxy, each Ar and C- ^ alkoxy is optionally substituted by F, Cl, alkyl, R 3 -S (O) 2 -, -CM, -C (O) -NH ( R 3 ) and C1.3 alkoxy;
    [0032] L is a linker chosen from a link, O,> C (O),
    6/118
    -CH 2 -, -O-CH 2 -, -NH-, -NH-CH 2 -, -CH 2 -NH-, -C (O) -NH-CH 2 -, -NH-C (O) NH - and -N (R 3 ) -S (O) m -;
    [0033] Ar is phenenia, pyridinyl, pyridazinyl, pyrimidinyl, pírazínüa, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazclíla, benzothíazolila, píperidinila, páperaziníl or a very pharmaceutically or very acidic.
    [0035] In another embodiment, a compound of formula (1) is provided according to any of the embodiments here previously and in which [0036] Cy is phenyl or pyridinyl, each of which is replaced by R 2 and optionally replaced by F, CI_ 2 Cl or alkoxy;
    [0037] R 2 is chosen from:
    [0038] L-Ar and C t . 3 alkoxy, each Ar and C v3 alkoxy is optionally substituted by F, Cl, C M alkyl, CH 3 -S (O) 2 -, -CN, -C (O) -NH (R 3 ) and C->. 2 alkoxy;
    [0039] L is a linker chosen from a bond, O,> C (O), -CH 2 -, -O-CH 2 -, -NH-, -NH-CH 2 -, -CH 2 -NH -, -C (O) -NH-CH 2 -, -NH-C (O) NH- and -N (R 3 ) -S (O) m -;
    [0040] Air is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazoiil, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazollla or piperidinyl [0041] or a pharmaceutically acceptable salt thereof.
    [0042] In another embodiment, a compound of the formula (I) is provided according to any of the modalities hereinbefore and in which [0043] Cy is phenyl or pyridinyl, each of which is replaced by R 2 and optionally replaced by F, CI_ 2 Cl or alkoxy;
    [0044] R 2 is chosen from:
    [0045] L-Ar and Ci. 3 alkoxy, each Ar and C1.3 alkoxy is optionally substituted by F, Çí, alkyl, CH 3 -S (O) 2 -, -CN, -C (O) -NH ( CH 3 ) and
    7/118
    C2 .2 alkoxy;
    [0046] L is a connector chosen from a connection. O,> C (O), -CH r , -O-CH 2 -, -NH-, -NH-CH 2 -, -CH 2 ~ NH- ·, -C (O) -NH-CH 2 -, -NH-C (O> NH-eN (H) -S (O) 2 -;
    [0047] Air is phenyl, pyridinyl, benzoxazolyl or piperidinyl [0048] or a pharmaceutically acceptable outlet thereof.
    [0049] In another embodiment, a compound of the formula (I) is provided according to any one of the modalities hereinbefore and in which [0050] X 1 is a linker chosen from a bond and - (CH 2 ) n -;
    [0051] Y is chosen from:
    [0052] a spirocciçlo chosen from
    [0053] a heterocycle chosen from piperidinyl and pyrrolidine;
    [0054] and phenyl each heterocycle or phenyl substituted by an R 4 ;
    [0055] R 4 is
    [0056] being hydrogen p ' 5 where R 5 cannot be [0057] halogenated [0058] each R 5 is independently chosen from hydrogen, Cj-3 aiquila, halo aiquila, C; - 3 alkylC ··, ^ alkoxy, ~ CH 2 -heterocycle and
    8/118 heteroddo each heterocycle optionally substituted by F, Ci, OH and CH 3 -S (O) 2 - and each heteroddo chosen from pyrrolidinyl, piperidinyl, morpholinyl and 1,4-oxazepan, [0059] or one leaves pharmaceutically acceptable value.
    [0060] In another modality, a compound of the formula (I) is provided according to any of the modalities hereinbefore and in which [0061] Xi is an igniter chosen from a generation and - (€ Η 2 ) Π - ;
    [0062] Y is chosen from:
    [0063] a spiroddo chosen from
    [0064] a heteroddo chosen from piperidinyl and pyrrolidinium;
    [0065] and phenyl each heteroddo or phenyl substituted by an R 4 ;
    [0066] R 4 is
    IC to V-Nμη
    X 3 ~ halogen or hydrogen,, N.
    [0067] each R 5 is independently selected from hydrogen, Ci-3 alkyl, -CF 3, alkyl - C 3 CI_: _ 3 alkoxy, -CH 2 -heterocido and heteroddo heteroddo each optionally substituted with F, Cl, OH and CH 3 - S (O) 2 and each heterodite is chosen from pyrrolidinyl, piperidinyl and 1,4oxazepan, or a pharmaceutically acceptable salt thereof.
    [0068] In another embodiment, a compound of the formula is provided
    9/118 (I) according to any of the modalities here previously and where [0069] Çys is
    11/108
    [0070] or a pharmaceutically acceptable salt thereof.
    [0071] In another modality, a compound of formula (I) is provided according to any of the modalities here previously © where [0072] X-Y =
    11/118
    [0073] or a [0074] comes out pharmaceutically acceptable from it.
    [0075] In another embodiment, a compound of the formula (I) is provided according to any of the modalities hereinbefore and in which [0076] Ring A is:
    [0077] or a pharmaceutically acceptable salt [0078] In another embodiment, a compound of the formula (1) is provided according to any of the modalities hereinbefore and in which [0079] RingA is:
    12/118 [0080] or a pharmaceutically acceptable salt thereof.
    [0081] In another embodiment, a compound of the formula (l) is provided according to any of the modalities hereinbefore and in which [0082] Ring A is:
    NH S [0083] or a pharmaceutically acceptable salt thereof.
    [0084] In another embodiment, a compound of the formula (I) is provided according to any of the modalities hereinbefore and in which [0085] Ring A is:
    o [0086] or a pharmaceutically acceptable salt thereof.
    [0087] In another modality, a compound of the formula (!) Is provided according to any of the modalities here previously and where [0088] R 2 is [0089] L-Ar;
    [0090] L is a linker chosen from a bond, O, and -O [0091] n is 1-3;
    [0092] Ar is carbocycle or heterocyclop;
    [0093] or a pharmaceutically acceptable salt thereof.
    13/118 [0094] In another embodiment, a compound of formula (I) is provided according to any of the modalities here previously and where [0095] Ar is C 3 . 5 cycloalkyl or tetrahydrofuranyl;
    [0096] n = 1;
    [0097] or a pharmaceutically acceptable product.
    [0098] In another embodiment, a compound of the formula (I) is provided according to any of the modalities here before and in which
    L-Ar is ;
    [00100] or a pharmaceutically acceptable salt thereof.
    [00101] In another modality, a compound of formula (I) is provided according to any of the modalities here previously and where [00102] R 2 is:
    [00103], ~ och 2 ch 3 , -och 2 ch 2 ch 3 , -och 3 , -ocf 3 or - “OCH2CF3;
    [00104] or a pharmaceutically acceptable salt thereof.
    [00105] In another embodiment, the invention provides compounds in Table I that can be made in view of the general schemes, examples and methods known in the art.
    TABLE OF COMPOUNDS AND BIOLOGICAL ACTIVITY
    11/148
    Example Structure IC50deBTK (nM) HPLC method RT (min) m / z [M * H] 1 Co r ' z ^ / v V 1 i is — x Q 2600 THE 4.13 401.2 2 P NH 2 s = V ll, N '' X 0 33 THE 4.08 431.3 3 rbl cy ^ O J ο. □ 810 THE 4.06 431.3 4 -4 NH rS nh 2 = v O ^ -fF H; n, o - THE 2.56 382.4
    11/158
    Example Structure IC50deBTK <nM] HStodó deHPLC RT(min) m / z [M * H] 5 * Ί - THE 2.59 438.4 6 NH. 6 í > r4 IL ' N Ò-r QTHE 2.75 405.4 7 NH to ys -'- '''II / Ò T - THE 2.83 417.3 8 laughs Vn r nh, , w lL N - THE 2.61 391.2
    11/16
    Example Structure ICSOdeBTK (nM) HPLC method RT (min) m / z [M4-H] 9 QThe NH, J /[1> b-r0 14 THE 4.11 415.3 10 l / T ^ b o * / o <w h ri 1¾ 'V = 7 ° ví Q - THE 4.14 494.3 11 o / ; =: 'V ^ -HJ FV-fi NH., Li ΙλΓ 0 5500 THE 2.80 494.2 12 Q '^ s = O FÍ NH 2 b ^ <c <v y y O-ç ”o - THE 2.67 422.3
    11/178
    Excess Structure BTK IC5O (nM) HPLC method : RT(min) fan / z) ii t Ar[IVKH] 13 V r -> Z t 'k J 1 «x jr ~~“' r / z — X o - THE 2.56 409.3 14 (f NHj s = «Ò-r ·O 7800 THE 2.81 419.4 15 0 d nh z y = ^ La Z ~ A v. / N Y ^ '0: - THE 2.89 394.4 16 f 0 NH 2 XgaJ ó <# vt4 La ò <- 0 580 THE 2.77 365.3
    11/188
    Example Structure JC50cfe BTK (nM) Ί ‘Method-pity forHPLC RT (min) m / zPVKH] 17 0 ryá NH a o '^ y 0 4800 THE 2.60 418.4 18 ú 'r IMM : V— ~~ J * “V o - THE 2.72 371.4 19 X o o mh 2 yA ο < ίΓ ^ il / LzSf - THE 2.84 433.3 20 O ' j Q' u H Ci p W H> V '- \ O 30 THE 3.03 815.2
    11/198
    Example Structure IC50 ofBTK (nM) HPLC method RT (min) m / z[M + H] 21 N O / TV a fyl · · .. cAví 0 A f A /v.,/ õ 98 THE 2.85 466.3 22 / o -'Cr ^ 0 Nr,cAx iL a^ ~~~ y \ 7.6 THE 2.91 447.3 23 NH,r JIL aB 10 THE 2.97 434.3 24 QV k Λ I & íP z 'o 9.4 THE 3.02 451.3
    11/20
    Example Structure IC50 ofBTK (nW) HPLC method RT (min) m / z] WH] 25 0 ) 5.1 THE 3.03 527.3 26 F FJj /° nrsbr.0 22 THE 3.03 560.3 27 Qo NH O nh 2 O ^ qrÁ L * δν 0 300 THE 2.84 457.3
    11/21
    Example Structure BTK IC5Q (nM) HPLC method RT (min) m / z[Μ-ί-Η] 28 0 °NH, Xs = Z° i5^ • NcH 3.5 THE 2.85 429.3 29 ONH. V ^ 'C <OAH VIZ/ A N- ~ Z'0 3.2 THE 2.83 417.3 30 Çí/ —Z ° Â Ò1 57 THE 2.54 474.35 31 ρ · ^ Ο Λ l NH Ç ssd X 'io V'T 11 z N ò-Z Q ·· 80 THE 2.86 429.35
    11/22
    Example Structure BTC 1C50 (nM) HPLC method RT (min) m / z [M + H] 32 ONH ,. = sV11> á-X 0 150 THE 2.81 429.35 33 kÂk 1 2nd 9.7 THE 2.83 417.35 34 f-O »„, oXA, NN ^ / ^ SrO 21 THE 2.78 394.35 35 ó NH, 2 '• ^ : = - · 8 j 0.77 THE 2.96 444.3
    11/23
    Example Structure IC50 ofBTK (nW) HPLC method RT (min) m / z 36 / O 230 THE 2.67 474.3 37 _ ((w / == ^ z ~ í 0 38 THE 2.51 500.3 38 z-Λ the y °χχ ^ ΡB 13 THE 2.84 455.3 39 o nh 2 x ^ 'PN α 290 THE 2.65 377.2
    11/24
    Example Structure ICSOdeBTK (nM) HPLC method RT (min) mfzP + H] 40 H Í V 4.9 THE 2.89 443.2 41 A '- ^ ......Q 0.73 THE 2.99 456.3 42 oO 6 nh 2 Xe ^ N ~! * z Q NS k ^ z ^ N- ^ A ^ 64 THE 2.92 417.4 43 J / ¾ ^ o. = / Íí 1 k iÇh 1 Ã J í aF z- ^O 51 THE 2.93 429.4
    11/25
    Example Structure BTK IC50 (nM) HPLC method RT (min) m / zP * H1 44 P-0 rS L θ Vi Il n h 2 n ·· 'a Νγ ^ & 1 THE 2.68 392.4 45 nh 2 »= v 0 · V AJ 10 THE 2.83 431.4 46 f / NH -a = 7 Jl · 2 J O ^ vA I λ Ν HN-A D 1.2 THE 2.85 417.4 47 r o j: · 1 c · Á II Z N '' N vZNr * oj 10 THE 2.84 431.4
    11/26
    Example Structure BTK IC50 (nM) HPLC method RT (min) m / zWH1 48 i /O 90 THE 2.97 443.4 4950 O.the y_zr ^ CX á A-, P ò A ° 1803 THETHE 2.96 QX, ç ^ · ^ 1IJ f 2.98 434.3 51 f 1NH, Vs2i - Γ1, N firO 1.7 THE 3.00 434.3
    11/278
    Example Structure ICSOdeBTK (nM) HPLC method RT (min) m / zP + Hl 52 %ω — V ° ò 18 THE 3.02 446.3 53 % -z Z ^ S / T | fs V 2 Λλ, A 14 THE 3.00 446.3 54 «Oo NH, == V JL / n Κ2 ^ ~ Λ __ 0.73 THE 3.00 432.4 55 The Nh ^ C_V The cúqrV II ^ Q -N <o 6.6 THE 2.93 417.4
    11/28
    Example Structure IC50 déBTK (rt) HPLC method RT (min) m / z[M + H] 56 jO nh 2 Ò * ~~ NÍ 15 THE 2.95 429.4 57 7th 3.2 THE 2.99 446.3 58 RO(/ SA 1, N* ~ N................................ / "................. .; 1.1 THE 3.01 458.3 59 O y — Z / ã c r% XlSh ” 'ô 8.9 THE 2.75 429.4
    11/29
    Example Structure BTK IC50 (nM) I Method ofHPLC RT (min) m / z P $ + H] 60 NH: W / fÀ NH, | y N O '<^ o 41 THE 2.82 473.4 61 ΑΆ> - ci ° Ã α ° NH ó NHj 'ys®' · N A 780 THE 2.86 548.1 62 r> F f / H ,; Vs * 'L / N f Z ^ - \ 0 93 THE 2.97 435.3 63 F p-OA. <3 NH, the 3d K Uz <Q 660 THE 3.08 485.3
    11/30
    Example Structure IC50deBTK (nW) HPLC method RT (min) m / z [M + HJ 64 NH »; S ^ 0 1> Or 0 6500 THE 2.79 495.1 65 rQ, 0 fS n KIH 2 s ^ FA, 11 / / A, __ g 330 B 0.65 495.1 66 rM X NHj oF <Í L, N ^ -N Ofp b 43 THE 3.10 469.2 67 Q ÇrFX A ò J z <3 38 THE 2.95 447.3
    11/318
    Example Stanza 1050 ofBTK (nM) HPLC method RT(min) m / z [IVHHJ 68 rS ° nh 2 trhíA 1 A Ò-r s 41 THE 3.08 451.4 69 XV V> α NH. X ΛΓ La N- ~ X '~~ Z \ 0 43 THE 3.20 485.3 70 pW O NHj ο1 # ιΓ ^ íL z N / X O 45 THE 3.07 451.3 71 ò y χκχο rtf) f Γ 7 X / 2 - “Z O 14 THE 3.04 431.4
    11/28
    Example Structure BTK ICSO (nM) HPLC method RT (min) m / z | »H] 72 οNH, sfVO ^ vi | l aΟ 4 THE 3.04 431A 73 p ^ ÇZ ^ rS F N : H è G o / / ¾ z N- ~ -Z 0 9.3 THE 3.00 435.3 74 / ir 'O'ÁJ / r ^ L X F / S NH, N X o - THE 2.89 453.3 75 í ^ (j nh 2 ysv crArà IL / N o 6600 THE 2.91 442.3
    11/33
    Example Structure IC50 of. BTK (nM) HPLC Method RT (min) m / z P * H] 76 rQ/THE, %crV ^h>Ò-r 61 THE 2.92 442.4 77 O - QhK H'N— Q 1.9 THE 2.72 543.3 78 the JÍ4Q70 2.1 THE 2.95 472.2 79 Ç 6.4 THE 3.05 460.2
    11/34
    Example Structure IC50 ofBTK (hM) HPLC method RT (min) m / zP * H] 80 RO/'SIT A1>ΌO 0.93 THE 3.04 458.4 81 0O NH £. 1 7 »* k Cs 0.79 THE 2.91 458.3 82 % -Λ · - σί · c> x 2 THE 2 95 472.2 83 % V 7 <7γ '^ Ό ~ ο ° γ ζ ^ fj 1 2.1 THE 2.99 484.3
    11/35
    Example Structure IC50 ofBTK (nM) HPLC method mr (mm) m / z [M ^ HÍ 8485 o ,, ^ · : ΐκ y J ò 52 THE 3.10 474.2 O : = ; J y 0 300 THE 3.11 486.2 86 o- ^ O F NH 2 zrF ° ' A r F ^ y ~ 95 THE 3.03 457.4 87 τ · V í Jff · ^L -FII aF1| 4.3 THE 2.87 469.3
    36/118
    Example Structure IC50 ofBTK (nM) Method ofHPLC RT(min) m / z 88 p — CZ ^ rS NH 2 V == - '° iCS K o 21 THE 2.96 443.4- 89 pFZC A IjtHj == ^ 0 O N O 34 THE 2.98 455.3 90 The NHj Ç-sU f ) o z—- ã / / , = - ZN H 90 B 0.55 460.1 91 p '^ CZ / TV 0 Λ> η, ν · ^' ^ 0- 0.79 THE 2.94 470.3
    37/118
    Example Structure IC50 ofΒΊΓΚ (nM) HPLC method RT(min) m / z [M + H] 92 ρΌ A 'N .-: .. y = : ' Ávp J> «q A V y Z 0 0.89 THE 2.88 470.3 93 ONHj, ss ^ ’0- 33 THE 2.80 514.3 94 O. O, y-N ^ ___ ///NH., XsCo ^ yrATHERE0 8200 THE 2.75 436.3 95 γ'Α LF __ / ΝγΑ ϊϊί O 4600 THE 2.71 399.3
    11/38
    Example Structure IC50d © BTK (nM) Method ofHPLC RT(mm) m / z [M * H] 96 ζΤ - tA;° 5 the ti 4.8 THE 2.95 434.3 97 ONHjΛ 0: 0.8 THE 2.93 458.3 98 x Ato x -cjrnx ° í 0n 0.7 THE 2.69 515.4 99 0 o 1 »^ 'CW ^ M |. the x 3.2 THE 2.76 557.3
    39/118
    Example Structure IC50 ofBTK (nM) HPLC method RT (min) m / z [M + H] 100 r O Ní ^ Χγ4 Ν l “X / ·” 0.8 THE 2.63 501.3 101 p- ^ Q r% NH p . X; ^ C 'W, N1' 2 V Í * ^ - N oH 9.2 THE 2.71 445.4 102 X rs NH 2 s = - 'jl> Ζ Ά) --o 2.7 THE 2.83 457.3 103 0 r XWyXF 0 τ ') ^ z-4 z «o 2.8 THE 3.13 445.2
    11/40
    Example Structure SC50deBTK (nM) HPLC method RT (min) m / z[M + H] 104 4AΟ 19 THE 2.79 422.4 105 fi NHy>'> A / -AA t A [ 13 THE 2.77 410.3 106 /THE<7Nt-ι, y = v^ ΆιI ___ c 13 THE 2.81 422.4 107 TO 1 .-. A 2 < A J :: - ! = 4 A - 3.3 THE 2.81 422.4j
    417118
    Example Structure: ICSOdeBTK (nW) HPLC method RT (min) m / z pkH} 108 ΛΓ 7Xqrp; nQQ l · ^ o 14 THE 2.75 448.3 109 P ο-χ 0 F NiHj Xss ^ CA X <N 00 * ^ 24 THE 2.86 436.3 110 o í 'Όγ- = τΡ °: i /Z “4O 0.87 THE 3.09 457.3 111 THENH, X ^ ^ nri · hx '’N oH 16 THE 2.77 410.4
    42/118
    Example Structure IconBTK (nM) HPLC method RT (min) m / zPH-H] 112 0-4 ri NHj ° I> b ^ • N 0 H 6.7 THE 2.82 408.4 113 / nh 5 JG n h 2 n ^ 4 ¢ / A 4.3 THE 2.85 420.4 114 p-iO F% NH 2 1> o 3.4 THE 2.87 459.3 115 rf ... LF Çi ^ ó nh 2 cr> rr >. x> H / <N __ ..... — ..... Q 3.5 THE 2.82 462.3
    43/118
    Example Structure BTK IC50 (nM) HPLC method RT (mm) m / z[M + H] 116 p F ·% Lf l O NH, = Z X / o'Xr'Z 11 N X. Ail. X O * 12 THE 2.78 450.3 117 for NH. s »N j z CIVA Á> H, N 'Α ^ Ύ'Ζ · 0 u THE 3.52 459.2 118 PO A γπ 4 y = N ° Xr4 HaN ^^ x ^ 0.5 THE 3.49 471.2 119 w 2 Mn ° JL N h 2 n ^ X 11 THE 3.25 471.3
    44/118
    Example Structure 1C50 of STK (nM) Method ofHRLC RT(min) m / z [M + H] 120 Ô NH, s ^ N i> h 2 n O 3.5 THE 3.29 459.2 121 -The fS ΧΓ ηΛ .......... / Q 0.2 THE 3.13 472.2 122 C) V ^ <r p X / X 0 17 THE 2.91 471.3 123 rO 7 To Na. yr- 'I> H Y N Q 9.1 THE 2.88 459.3
    45/118
    Example Structure BTC 1CS0 (nM) Method ofHPLC RT (min) m / z [M * H] 124 Cl O 11 N Vz ~ N oH 10 B 1.73 444.1 125 ΰ ~ 7.5 8 0.85 424.0 126 OjryO 28 THE 2.98 424.3 127 p-7 rS '··, V == 7 o <i g <4 Ã Z N HjN' Μη 15 8 0.86 436
    46/118
    Example Structure IC50 ofBTK (nM) HPLC method RT (min) m / zJWH] 128 :P. ΓX XY b.0 0.9 THE 3.02 446.4 129 ó NH, X T / G ií'É, V t 0 29 8 0.85 446.1 130 r Γ 'X <> NH Z 0, À I $ H; N · «0 6.4 THE 3 434.4 131 £ F Xf ó nh 2 XX Q ^ XX A ^ 0κ.γχ o 28............... ί B 0.80 433.9
    47/118
    Example Structure IC50 ofBTK (nM) Method ofHPLC RT (min) m / zP + HJ 132 / 3 ó 'nh 2 CtTÁ JL A VÍ4 y% Õ 1.9 B 1.02 451.5 133 V rs NH, c <VIDE íl Z N HX ^ N y ^ / Λ 8.4 THE 2.64 368.3 134 THEdNHj: eZ> i''íII NQ ok 120 B 0.59 438.3 135 V F X. NH; XíA 1 a ^ N 'Ã' ·· ^ & v 26 THE 2.83 454.3
    48/118
    Example Structure ICSO ofBTK (nM) | Method ofHPLC r .................RT(min) m / z [M + H] 136 z P „, p 0 IiÁ Η χ ^“ N 14 B 0.91 466 137 F f J- F fW * X, Ari 7 Λ 1.6 B 0.89 494.1 138 > 5 NH * s ^ Ü * SpN% - 0 2.2 B 0.86 440.1 139 _ o X = A y s 16 B 0.56 428.1
    11/49
    Example Structure IC5G déBTK (nM) HPLC method RT (min) m / z [M + Hl 140 Vo XXzaXXjà — Z VV -r *O 0.9 . B 0.90 436.2 141 p: P x4 ~ f F. / w ¢ 1¾ sS < 0 1 $ O ; -— ....... Q 14 B 0.87 450.0 142 AÁoH 29 B 0.82 438.0 143 FEDERAL POLICEFFi0 37 B 0.85 450.0
    50/118
    Example Structure ! C50 fromBTK (nM) Method ofHPLC RT(min) m / z (M + HJ 144 XH ; . : = F 0 jA «Η 72 B 0.80 438.1 145 oy b nh 2 y = y crsfC J! y ΗΛ '· ΙΪ v 0 3.5 THE 3.17 458.4 146 and F X O o N! -t 2 V I . <<1 22 THE 2.95 482.4 147 ^. F A NH ysX JI τ o> ^ - P 9.2 B 0.84 432.0
    51/118
    Example Structure BTK IC5Õ (nW Method ofHPLC RT (min) m / z[M * H] 148 . p ~ r vk <7 nh y = ^ J / õ < v> Y ~ ' 3.0 THE 3.03 456.3 149 y k '^ 5.M) ™ -O 100 B 0.78 480.4 150 o- ^ CZ / NH. e 'y ^ H / T ^ í 1' X ^ hk | l · 0.8 B 0.83 471.2 151 O OvyCP<7O 0.7 8 0.78 471.3
    11/118
    I)Example Structure IC50 ofBTK (nM) method ofHPLC RT (min): m / z(M-í-H] 152 b kYu zP^ sz / ^ χ ίflM 1.5 B 0.73 459.3 153 The ~ΛΎ> => 'cYYYs jl>'K& 2.3 B 0.68 396.1 154 > ° I k ^ Y for> k / YzMi / ~ Vfe * 0.6 B 0.71 408.3 155 / 0 o NH 2 : = - · ' 0Í bíV Η, Ν ·''/ ' Q 7.3 B 0.69 396.2
    53/118
    Example Structure ICSOdeBTK (nM) HPLC method RT (mm) m / z[M + HJ 156 Ο-Ά3 · Á NH .. s = 7 0 1¼ K Q 16 B 0.70 420.4 [M-HJ + 157 1 - H "°O 2.0 B 0.86 434.6 158 CTONH .. = 4J®o 'W liiqbr ^ b. ^Q 6.3 B 0.80 442.1 159 0 rS wh y = </ ci | [N } V * ! K 0: 20 B 0.75 430.2
    54/118
    Example Structure ICSOdeBTK (nM) HPLC method RT (min): m / zW + Hl 160 ο — χ ' ρ lf nh 2 ''Λ-Ά<y'VÍ1> HX ' V o. 1.4 B 0.87 462.1 161 O έ έ y = ^ cF><F1> h 2 n '< ^^ O; 1.1 B 0.87 454,462.8 162 / ! J - *. ™ õ; V · L · Z — SHA '..- d lx ^ F 1 o 1 9.2 B 0.91 450.2 163 Çf p NH, = U oFF Π ; .N ι ^ ν '^' Ί <'> e: 4.8 B 0.86 464.5
    55/118
    Example Structure ·] ................................................ ..1K5 BTK (nM) HPLC method RT (mm): m / z [M + H] 164 v. 0.5 B 0.90 476.2 165 T O. X// 15 8 0 89 440.2 [M-HJ +443.2 166 r Nl-tg = S / Ο * | Γ% o o 6.6 B 1.06 420.3 167 nh 2 = a 1 A αχ 0 0.9 B 0.75 422.2
    56/118
    Example Structure lC50deBTK (nM) HPLC method RT (min) m / z[MtH] 168 O * z ”** > There *** ^ · : Jl>'b''' 1.2 B 0.84 436.3
    00106] or the pharmaceutically acceptable salts thereof.
    [00107] The present invention also relates to metabolites, and prodrugs of compounds of the formula (I).
    The present invention also relates to a pharmaceutically acceptable salt of a compound of formula (I) with inorganic or organic acids or bases.
    [00109] In another aspect, the invention relates to the compounds of formula (I) - or the pharmaceutically acceptable salts thereof as medicaments.
    [00110] In another aspect, the invention relates to the compounds of formula (I) - or the pharmaceutically acceptable salts thereof for use in a method for treating a patient.
    [00111] In another aspect, the invention relates to the compounds of formula (I) - or the pharmaceutically acceptable salts thereof for use in the treatment of autoimmune diseases and allergic disorders.
    [00112] In another aspect, the invention relates to the use of compounds of formula (I) - or the pharmaceutically acceptable salts thereof - to prepare a pharmaceutical composition for the treatment of autoimmune diseases and allergic disorders.
    [00113] In another aspect, the invention relates to a method for the treatment of autoimmune diseases and allergic disorders comprising
    57/118 by administering a therapeutically effective amount of a compound of formula (I) - or one of the pharmaceutically acceptable salts thereof - to a patient.
    [00114] In another aspect, the invention relates to a pharmaceutical preparation containing as active substance one or more compounds of formula (I) - or the pharmaceutically acceptable salts thereof optionally in combination with conventional excipients and / or vehicles.
    Definitions [00115] Terms that are not specifically defined here have the meanings that are evident to man versed in the light of the global description and the context as a whole.
    [00116] When used herein, the following definitions apply, unless otherwise stated:
    [00117] The use of the prefix C x . y , where x and y each represents a natural number, indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, can consist of a maximum of y and a minimum of x carbon atoms.
    [00118] Alkyla denotes monovalent, saturated hydrocarbon chains, which may also be present in the form of a linear (unbranched) and branched chain. If an aiquila is substituted, the substitution can occur independently of each other, by mono- or polysubstitution in each case, in all carbon atoms carrying hydrogen.
    [00119] For example, the term CAalkyl includes, for example, H 3 C-, H3C-CH2- H 3 C-CH 2 -CH 2 -, H 3 C-CH (CH 3 ) -, h 3 c-ch 2 -ch 2 -ch 2 -, h 3 cCH 2 -CH (CH 3 ) -, H 3 C-CH (CH 3 ) -CH 2 -, H 3 CC (CH 3 ) 2 -, h 3 c-ch 2 -ch 2 -ch 2 CH 2 -, H 3 C-CH 2 -CH2-CH (CH 3 ) -, H 3 C-CH 2 -CH (CH 3 ) -CH 2 -, H 3 C-CH ( CH 3 ) ΟΗ 2 -ΟΗ 2 -, H 3 C-CH2-C (CH 3 ) 2 -, H 3 CC (CHs) 2 -CH 2 -, H 3 C-CH (CH 3 >
    11/58
    CH (CH 3 > and H 3 C-CH 2 -CH (CH 2 GH 3 ) -.
    [00120] Other examples of alkyl are methyl (Me; -ΟΉ 3 ), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH 2 CH 2 CH 3 ), 2-propyl ( i-Pr; isopropyl; -CH (CH 3 ) 2 ), 1-butyl (n-butyl; n-Bu; -CH 2 CH 2 CH 2 CH3), 2-methyl-
    1- propyl (/ so-butyl; / -Bu; -CH 2 CH (CH 3 ) 2 ), 2-butyl (sec-butyl; seo-Bu; -CH (CHs) CH2CH 3 ), 2-mefiF2-propyl (tert-butyl; PBu; -C (CH 3 ) 3 ), 1 pentium (n-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (CH (CH3) CH 2 CH 2 CH 3 ) 1 3-pentyl (-CH (CH 2 CH 3 ) 2 ), 3-methyl-1-butyl (/ sopentyl; -CH 2 CH 2 CH (CH 3 ) 2) ) 2-methyl ~ 2-butyl (-Ο (ΟΗ 3 ) 2 ΟΗ 2 ΟΗ 3 ), 3-methyl-
    2- butyl (-CH (QH 3 ) CH (GH 3 ) 2 ) j 2,2-dimefil-1-propyl (neo-pentyl; CH 2 C (CH3) 3 ), 2-methyl-1-butyl (- CH 2 CH (CH 3 ) CH 2 CH 3 ), 1-hexyl (nhexyl; -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH (CH 3 ) CH 2 CH 2 CH 2 CH3),
    3-hexyl (-CH {CH 2 CH 3 ) (GH 2 GH2CH3)), 2-metH-2-pentyl (-
    C (CH 3 ) 2CH2CH 2 CH 3 ) ! 3-methyl-2-pentyl (-CH (CH 3 ) CH (CH 3 ) CH 2 CH 3 ) 1 4 methyl-2-pentyl (-CH (CH 3 ) CH 2 CH (GH3) 2 ), S-methyl- S-pentia (C (GH 3 ) (CH 2 CH 3 ) 2 ), 2-ρΐβ0Ρ3-ρ6η0ί3 (-CH (CH 2 CH 3 ) CH (CH 3 ) 2) I 2,3dimethi-2-butyl (-G (CH 3 ) 2 GH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (CH (CH 3 ) C (CH 3 ) 3 ), 2,3-dimethyl-1-butyl (-CH 2 CH (CH 3 ) CH (CH 3 ) CH 3 ), 2,2dimethyl-1-butyl (-CH 2 C (CH 3 ) 2 CH 2 CH 3 ), 3,3-dimethyl-l-butyl (CH 2 CH 2 C (CH 3 ) 3 ), α-methyl-pentyl (-CH 2 CH (CH 3 ) CH 2 CH 2 CH 3 ), 3-methyl 1-pentyl (-CH 2 CH 2 CH (GH 3 ) CH 2 CH 3 ), 1-heptyla (π-heptyla), 2-methyl-1-hexiia, 3-methyl-1-hexiia, 2,2-dimethyl! -1-pentyl, 2,3-dimethyl-pentyl, 2,4-dimethyl-1- pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethylpentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decila (n-decila) etc. [00121] By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decila etc. without any further definition, saturated hydrocarbon groups with the corresponding number of carbon atoms are desired, in which all isomeric forms are included.
    [00122] The above definition for alkyl likewise applies
    59/118 if the alkyl is part of another (combined) group such as, for example, C x . y aliquiiamino or C x _ y alkoxy.
    [00123] Unlike alkyl, alkenfla consists of at least two carbon atoms, in which at least two adjacent carbon atoms are joined together by a double bond of CC and a carbon atom can only be part of a double bond of CC. In an alkyl as defined hereinbefore having at least two carbon atoms, two hydrogen atoms in adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenyl is formed.
    [00124] Alkenyl may optionally be present in the eis or trans or E or Z orientation with respect to the double bond (s).
    [00125] Unlike alkyl, alkynyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as defined hereinbefore having at least two carbon atoms, two hydrogen atoms in each case in adjacent carbon atoms are formally removed and the free valences are saturated to form two other bonds, the corresponding alchemy is formed.
    [00126] Haioalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms in the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. A haloalkyl (haloalkenyl, haloalkynyl) must also be substituted, substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms carrying hydrogen.
    60/118 (00127] Examples of haloalkia (haloalkenyl, haioalkynyl) are CF 3í -CHF , -CH 2 F, -CF 2 CF 3 , -CHEGES, -CHAGES, -CF 2 CH 3 , -CHFCH 3 , -CF 2 CF 2 CF 3 , -CF 2 CH 2 GH 3 , -GF = GF 2 , -CC1 = CH 2 , -CBr ™ CH 2 , -C = C-ÇF 3 , -CHFCH 2 ÇH 3 , -CHFCH 2 CF 3 etc., [00128] Hyogen refers to fluorine, chlorine, bromine and / or iodine atoms.
    [00129] Cycloalkyl is made from the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings, two rings are joined together so that they have at least two carbon atoms together, [00130] If a cycloalkyl must be replaced, the substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case , in all carbon atoms carrying hydrogen. Cycloalkyl itself can be linked as a substituent for the molecule through each appropriate position of the ring system.
    [00131] Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oiolo-heptyla. Corresponding groups are an example:
    cyclohexyl [00132] Spirocycle is a spiro-hydrocarbon ring, a carbon atom (spiroatom) belongs to two rings together.
    [00133] Arila denotes mono, bi or tricyclic carbocycles with at least one aromatic carbocycle.
    [00134] Preferably, it denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or a six-membered ring with a five-membered ring), where the second ring
    61/118 may likewise be aromatic or, however, may likewise be saturated or partially saturated.
    [00135] If an arifa is to be replaced, the substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms carrying hydrogen. Aryl itself can be attached as a substituent to the molecule through each appropriate position in the ring system.
    [00136] Examples of aryl are phenyl and naphthyl.
    [00137] The above definition of aryl likewise applies if aryl forms part of another (combined) group, for example, in arylamino, aryloxy or arylalkyl.
    [00138] Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkia or spirocyclic by replacing one or more of the -CH 2 groups - independently of each other in the hydrocarbon rings by the groups -O-, -S- or -NH -, in which a total of no more than five hetero atoms can be present, at least one carbon atom can be present between two oxygen atoms and between two sulfur atoms or between an oxygen and a sulfur atom and the ring as a whole it must have chemical stability. Hetero atoms can optionally be present in all possible oxidation stages (sulfur sulfoxide -SO-, sulfone -SO 2 ; nitrogen - »N-oxide).
    [00139] A heterocyclyl is substituted, substitutions can occur independently of each other, in the form of mono or polysubstitutions in each case, in all nitrogen and / or carbon atoms carrying hydrogen. Heterocyclyl itself can be attached as a substituent to the molecule through each suitable position of the ring system.
    [00140] Examples of heteroclclylation are tetrahydrofuranyl, tetra
    62/118 hidropiranila, piperidiniía, piperazinila, pírrolidiniía, morpholínila, or the following heterocyclic spirocycles
    [00141] Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring. that compared to the corresponding aryan or cycloalkyl, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently from each other among nitrogen, sulfur and oxygen, in which the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system.
    [00142] If a heteroaryl should be replaced, the substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all nitrogen and / or carbon atoms carrying hydrogen. Heteroaryl itself can be linked as a substitute to the molecule through each suitable position of the ring system, both carbon and nitrogen.
    [00143] Examples of heteroaryl are, pyridinyl, pyridazinyl, pyrimidinyl, pírazine, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl, and the like.
    [00144] Heteroatoms can optionally be present and all possible oxidation stages (sulfur -> sulfoxide -SO-, sulfone -SO 2 ; nitrogen -> N-oxide).
    [00145] Carbocycles include hydrocarbon rings containing three to twelve carbon atoms. These carbocycles can be
    63/118 of aromatic or non-aromatic ring. Non-aromatic ring systems can be mono- or polyunsaturated. Preferred carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenium, cyclohexyl, cyclohexenyl, cycloheptaniy, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutany, dihydronaftil, tetrahydrone, tetrahydrone -hydronaffila, benzocycloheptanil and benzocycloheptenyl, [00146] All cyclic and acyclic systems defined in this section hereinbefore should be understood as opdonally partially or completely halogenated where possible and unless otherwise indicated.
    Stereogenesis / soivates / hydrates: Unless specifically stated, throughout the specification and appended claims, a given chemical formula or name must cover taütomers and all stereoisomers, optical and geometric isomers (eg, enantiomers, diasteromers, E / Z isomers) , etc.) and racemates of the same as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any previous forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof. The compounds and salts of the invention can exist in unsolvated forms as well as solvated with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms such as hydrates are considered equivalent to unsolvated forms for the purposes of the invention.
    [00147] Salts: The phrase pharmaceutically acceptable and used here to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of safe medical diagnosis, suitable for use in contact with human tissues and animals without excessive toxicity, irritation, allergic response
    64/118 ca, or other problem or complication, and commensurable with a reasonable benefit / risk ratio.
    [00148] When used herein pharmaceutically acceptable salts refer to derivatives of the described compounds in which the parent compound is modified by preparing base or acid salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; and the like.
    [00149] For example, such salts include acetates, ascorbates, benzenesuifonates, benzoates, besylates, bicarbonates, bitartrates, bromides / hydrobromides, Ca-edetates / edetates, cansilates, carbonates, chlorides / hydrochlorides, citrates, edisylates, ethane disuifonates, stolates , fumarates, giuceptates, gluconates, glutamates, glycolates, glycoli narsnylates, hexylresorcinates, hydrabamines, hydroximaleates, hydroxin phosphates, iodides, isothionates, iactates, lactobionates, mayates, maleates, metatylsates, methylates, methylates, methanesylates, methanesates, methanates, methanates, methanates, methylates , oxalates, pamoates, pantothenates, phenyl acetates, phosphates / diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulphamides, sulphates, tannins, tartrates, theoclates, teluenesulphonates, trietiodides, ammonium, benzathines, chloroprops, chloroprops, chlorines etiphenodiamines, meglumirias and procaines.
    [00150] Other pharmaceutically acceptable salts can be formed with cations of metals such as aluminum, calcium, iithium, magnesium, potassium, sodium, zinc and the like (likewise see, Pharmaceutical salts, Birge, SM et al, J. Pharm. Scí ., (1977), 66, 1-19).
    [00151] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic portion by conventional chemical methods. Ge
    65/118 such salts can be prepared by reacting the free base or acid form of these compounds with a sufficient amount of the appropriate base or acid in agia or in an organic diluent such as ether, ethyl acetate, ethaneL isopropanol, or acetonitrile , or a mixture of them.
    [00152] Salts of acids other than those mentioned above which, for example, are useful for purifying or isolating the compounds of the present invention (for example, trifluoroacetates), likewise comprise a part of the invention.
    [00153] Some abbreviated notations and their corresponding structures are listed below;
    [00154] In a representation such as, for example
    -Ô, [00155] the solid line means that the ring system can be attached to the molecule via carbon atom 1, 2 or 3, and is thus equivalent to the following representation
    [00156] By a therapeutically effective amount for the purposes of this invention is meant an amount of substance which is capable of preventing symptoms of disease or alleviating these symptoms, or which prolongs the survival of a treated patient.
    LIST OF ABBREVIATIONS
    B.C Acetia ACN Acetonitrile aq Aqueous ATP Adenosine triphosphate Bn Benzila Bu Butila Boc terc-butHoxicarbonyl
    66/118
    cat Catalyst cone focused d day (s) TLC Thin layer chromatography DEA N } A-di-isopropi letila mi na DMAP 4-N, A-dimetnaminopyridine DME 1,2-dimethoxyethane DMF N, N-dimethylformamide DMSO Dimethiisulfoxide dppf 1,1'-bis (diphenylphosphino) ferrocene EDC 1 -Ethii-3 ”(3-dimethylaminopropyl) carbodiimide ESI electrolysis spraying Et Ethyl Et 2 O dieti I ether EtOAc ethyl acetate EtOH Ethanol H hour (s) HATU O- (7-azabenzotnazole-1-H) -A hexafluorophosphate A. A, Atetramethyl-uronium Hep Heptane HPLC high performance liquid chromatography / Iso LC liquid chromatography □ HMDS lithium bis (trimethylsilyl) amide sin. Solution mCPBA 3-chloroperoxbenzoic acid Me Methyl MeOH Methanol min Minutes MPLC medium pressure liquid chromatography MS mass spectrometry MBS A-bromo ~ succinimid N1S A-iodo-succinimide NMM A-methylmorphine
    67/118
    NMP A / -methylpyrrolidone NP normal phase At. not available PBS phosphate buffered saline Ph Phenyl Pr Propyl Pyr Pyridine rac Racemic Rf (Rf) retention factor RP reverse phase RT Retention time (HPLC) rt room temperature TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBME tert-butylmethylether TBTU O- tetrafluoroborate (benzotriazole-1-yl> N, N, Ν ', N' ~tetramethyluronium tBu tert-butyl TEA Tríetiiamjha temp Temperature tert Tertiary Tf Tritlate TFA trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl TRIS trisÇhydroxymethylj-amine methane Ts p-Tosila TsOH p-toluenesulfonic acid UV Ultraviolet
    Ό0157] Aspects and advantages of the present invention will become evident from the following detailed examples that illustrate the fundamentals of the invention by way of example without restricting its scope:
    PREPARATION OF COMPOUNDS ACCORDING TO THE INVENTION
    68/118
    GENERAL SYNTHETIC METHODS [00158] Ideal reaction conditions and reaction times may vary depending on the particular reagents used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions can be easily selected by someone of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Intermediates and products can be purified by chromatography on silica gel, recrystallization and / or reverse phase HPLC (RHPLC). Discrete enantiomers can be obtained by resolving racemic products using chiral HPLC RHPLC purification methods used anywhere from 0-100% acetonitrile in water containing 0.1% formic acid or 0.1% TFA and used in one of the following columns: [00159] a) Waters Sunfire OBD Cl 8 5 pm 30x150 mm column.
    [00160] b) Waters XBridge OBD C18 column 5 pm 30x150 mm.
    [00161] c) Waters ODB C8 column 5 pm 19x150 mm.
    [00162] d) Waters Atlantis ODB C18 column 5 pm 19x50 mm, [00163] e) Waters Atlantis T3 OBD column 5 pm 30x100 mm.
    [00164] f) Phenomenex Gemini Axia C18 column 5 pm 30x100 mm. HPLC methods:
    Analytical LC / MS Analytical Method A:
    Column: Thermo Scientific column, Aquasil C18, 50 x 2.1 mm, 5 pm Gradient:
    Time (min) 0.1% Formic Acid in Water 0.1% Formic Acid in ACN Flow (ml / min) 0 90 10 0.5 0.5 90 10 0.5 1.5 1 99 0.5
    69/118
    Time (min) 0.1% Formic Acid in Water 0.1% Formic Acid in ACM Flow (min / min) 2.5 1 99 0.5 3.3 90 10 0.5 4.0 90 10 0.5
    Analytical LC / MS Analytical Method B:
    Column: Waters BEH 2.1 xSOmm C18 1.7 pm column
    Gradient:
    Time (min) 95% Water / 5% ACN (0.05% TFA) ACM (0.05% TFA) Flow (ml / min) 0 90 10 0.8 1.19 0 100 0.8 1.7 0 100 0.8
    Ό0165] The compounds according to the invention are prepared by the methods of synthesis described hereinafter where the substituents of the general formulas have the meanings given here above. These methods are understood as an illustration of the invention without restricting its subject matter and the scope of the claimed compounds for these examples. Where the preparation of starting compounds is not described, they are either commercially obtained or can be prepared analogously to the known compounds or methods described herein. Substances described in the literature are prepared according to published methods of synthesis.
    [00166] The compounds of formula I can be prepared as shown in Scheme Ia and Ib below.
    70/118
    Scheme 1a
    Py lg!
    [00167] In scheme Ia, a heterocycle A is treated with a suitable base and reacted with a group X r Y containing a leaving group (LG) B to provide the compound of the general formula (I).
    Scheme 1b:
    Y
    [00168] In the scheme lb, C (where X - O, N, S or NH 2 ) is condensed with D to provide the compound of the general formula (I).
    SYNTHETIC EXAMPLES
    Method 1
    Synthesis of Intermediate 1 -1
    TsClTEA, DMAP
    CH GI S [00169] A solution of R-1 (5.0 g, 23 ml) in CH 2 CI 2 is treated with TEA (6.5 mL, 47 mmol) and DMAP (0.57 g, 4.7 mmol ). The mixture is stirred for 24 h then concentrated in vacuo.
    [00170] The residue is dissolved in EtOAc and washed with saturated aqueous ammonium chloride and brine. The organics are collected and
    71/118 volatiles are removed in a vacuum. The crude residue is triturated with Et 2 O and the solid filtered and collected to provide 1-1 (5.6 g, 65%) m / z 367.9 [M +].
    [00171] The following intermediates were prepared in a similar manner.
    Structure Intermediate m / z OTs Λ X o 1-2 396.3 [M + H] JXO 1-3 356.0 [M + Hl
    Method 2
    Synthesis of Intermediate I-4 and separation of diastereomers I-5 and I-6.
    R-6 I-4 1-5! -6 [00172] In a solution of PPh 3 CH 3 Br (578 g, 1.62 moi) in THF (3.5 L) a solution of n-Buü ( 600 mL, 1.5 mol) at -78 ° C under N 2 . The mixture is stirred at 0 ° C for 1 h, then R-2 (200 g,
    72/118
    1.08 mol) in THF (2.0 L) is added to the reaction mixture at 0 ° C. The mixture is allowed to warm to room temperature, stirred for 1 h, then poured into H 2 O and extracted with EtOAc. The organic layers are washed with brine, dried with concentrated Na 2 SO 4 and purified by flash chromatography (SiO 2s Hep 25% EtOAc in Hep) to produce compound R-3 (70 g, 36%).
    [00173] In a solution of R-3 (20 g, 109 mmol) in Et 2 O (150 mL) Zn-Cu (56.2 g, 436 mmol) is added at 10 ° C under N 2 . Trichloroacetyl chloride (39.7 g, 218 mmol) in DME (150 mL) is added. The mixture is allowed to warm to room temperature and stir for 2 days. The mixture is treated with aqueous NaHCO 3 and extracted with EtOAc. The organic layers are washed with brine, dried with Na 2 SO4, concentrated and purified by flash chromatography (SiO 2 , 25% Hep EtOAc in Hep) to produce R-4 (11 g, 34%).
    [00174] In a solution of R-4 (35.5 g, 121 mmol) in saturated NH 4 CI (64.7 g, 1.21 mol) in MeOH (400 ml.) Zn (79.1 g) is added , 1.21 mol). The mixture is stirred at room temperature for 8 h. The mixture is treated with H 2 O and extracted with EtOAc. The organic layers are washed with brine, dried with Na 2 SO 4 , concentrated and purified by flash chromatography (SiO 2 , 25% Hep EtOAc in Hep) to provide R-5 (19 g, 69%).
    [00175] To the mixture of R-5 (19 g, 84.3 mmol) in THF (200 mL) NaBH 4 (12.8 g, 337.2 mmol) is added at 0 ° C and then stirred at room temperature for 6 h. The mixture is treated with MeOH and H Z O, then extracted with EtOAc. The organic layers are washed with brine, dried with Na 2 SO 4 , concentrated and purified by flash chromatography (SiO 2 , 50% Hep EtOAc in Hep) to produce R-6 (12 g, 63%).
    [00176] To the mixture of R-6 (22 g, 96.8 mmol) and pyridine (23.2 g, 290.4 mmol) in CH 2 CI 2 (300 mL) is added TsCI (27.7 g. 145 , 2 mmol) at
    73/118
    0 ° C and then stirred at room temperature overnight. The mixture is treated with H 2 O and extracted with EtOAc. The organic layers are washed with brine, dried with Na 2 SO 4 , concentrated and purified by flash chromatography (SíO 2 , 40% Hep EtOAc in Hep) to yield 1-4 (26.6 g, 72%) m / z 382.2 [M + H]. 1-4 is separated by flash chromatography (SiO 2 , 40% Hep EtOAc in Hep) to produce 1-5 diastereomers (mlz 382.2 [M + H]) and 1-6 (mtz 382.2 [M + H ]).
    Method 3
    Synthesis of Intermediate 1-8
    [00177] In a solution of R-7 (15.0 g, 97 mmol) in CH 2 I 2 (350 mL) isoamylnitrite (58.7 g, 580 mmol) is added. The solution is stirred for 15 min at room temperature then heated to 70 ° C for 2 h. The mixture is cooled to room temperature then divided between EtOAc and aqueous sodium bisulfite. The organics are collected, dried over MgSO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 50% Hep EtOA in Hep) to yield 1-7 (13.1 g, 51%) m / z 266.8 [M + f IJ.
    [00178] A solution of 1-7 (2.0 g, 7.5 mmol), 4-phenoxypheniboronic acid (2.0 g, 9.3 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (H ) (1.5 g, 2.1 mmol) in DMF (20 mL) and Cs 2 CO 3 aqueous 2M (10 mL) is heated at 120 c C for 2h. The mixture is cooled to room temperature, then divided between EtOAc and aqueous NH 4 CI. The organics are collected, dried over MgSO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 10-30% EtOAc in Hep) to yield 1-8 (1.6 g, 69%). m / z 309.1 [M + H]
    74/118
    Method 4
    Summary of Intermediate 1-9
    F -8 i-9 [00179] In malonitrile (7.55 g, 114 mmol) in THF (200 mL) at 0 ° C, sodium hydrate (60% dispersion in mineral oil, 4.57 g, 114 mmoi) slowly under a stream of nitrogen. After 10 min, R-8 (27 g, 115 ml) is added and the geo bath is removed. The mixture is stirred at room temperature for 1.5 h, then dimethysulfate is added, then heated to reflux for 2 h. The mixture is cooled to room temperature, then triethylamine and hydrazine are added.
    [00180] The mixture is heated to reflux for 2 h, then concentrated in vacuo, diluted with water and extracted with 10% MeOH in EtOAc. The organics are collected, dried over MgSO 4 , filtered and concentrated. The crude is purified by flash chromatography (SiO 2 , 0-100% EtOAc in Hep) to provide I-9 (5.7 g, 18%). m / z 277.5 [M + Hj
    Method 5
    Synthesis of Intermediate 1-10
    N
    í-i no [00181] In a solution of 1-1 (200 mg, 0.54 mmoi) in DMSO
    75/118 (2.5 mL) KCN (71 mg, 1.1 mmol) was added. The mixture was heated to 100 ° C for 18 h, then cooled to room temperature and partitioned between EtOAc and water. The organics were collected, dried over MgSO 4j filtered and concentrated in vacuo to provide MO (quant, 120 mg), m / z 223.1 [M + H] [00182] The following intermediates were prepared in a similar manner
    Structure Intermediate m / z M iii vN Λ o H1 181.0 [M-fBu] NMyO0 M2 211.1 [M + H] δ M3 195.4 [M-tBu] .......................................... ..........
    Method 6
    Intermediate Synthesis 1-14
    MO M4 [00183] In a solution of 1-10 (250 mg, 1.1 mmol) in DMF (2
    76/118 mL) 20% (w / w) aqueous NH 2 S (2 mL, 5.9 mmol) is added. The mixture is stirred at room temperature for 17 h, then diluted with water. The resulting white is filtered and collected to yield 1-14 (160 mg, 55%). m / z 257.0 [M + H] [00184] The following intermediates were prepared in a similar manner
    Structure Intermediate m / z h 2 n ^ s o 1-15 271.1 [M + H] KJM ^ SV-NO 1-16 189.0 [M-tBlí] H 2 N „^ S M7 245.0 [M + H] u Ç) '^ O M8 285.1 [M + H]
    Method 7
    Intermediate Summary 1-19
    77/118
    M3 MS
    OH [00185] A solution of M3 (422 mg, 1.69 mmol) in EtOH (8.4 ml) is treated with 50% (w / w) aqueous hydroxylamine (1.1 ml, 16.9 mmol). The solution is heated to 70 ° C for 2 h, then the volatiles are removed in vacuo to provide 1-19 (478 mg, quant) m / z 284.1 [M + HJ.
    [00186] The following intermediates were prepared in a similar manner
    intermediate m / z ÇH Η 2 ΝγΝ L-NyO 1-20 244.1 [M + H]
    Wétodo 8
    Intermediate Summary 1-21
    121 [00188] In a solution of I-8 (200 mg, 0.65 mmol) and Cs 2 CO 3 (423 mg, 1.30 mmol) in DMF (3 mL) is added 1-1 (262 mg, 0 , 71 mmol). The mixture is heated at 60 ° C for 18 h, then concentrated in vacuo. The residue is purified by flash chromatography (SiO 2 , Hep at
    78/118
    50% EfOAc in Hep) to yield 1-21 (217 mg, 66%) m / z 504.2 [M + H].
    [00189] The following intermediates were prepared in a similar manner:
    Structure Intermediate m / z / O 0 yY Í T o Q ^ X · 1-22 492.2 [M + H] 0— / - fo w o-4 rí '—φί) = O 1-23 518.2 [M ^ H] o ~ .Z ~ Ú o / 7 V L ... o 8 U .. N q) 1-24 518.2 [M + H] Ίl 1-25 AT
    79/118
    Method 9
    Summary of Intermediate 1-26
    [00190] In a solution of 1-6 (800 mg, 2.6 mmol) in THE (40 mL) is added R-8 (650 mg, 3.0 mmol), tri-n-octyl phosphine (3.0 g , 8.0 mmoBeADDP (1.1 '- (azodicarbonyl) dipiperidine) (2.1 g, 8.2 mmol). The mixture is stirred for 48 h, then concentrated in vacuo. The residue is partitioned between saturated aqueous NH4CI and EtOAc. The organics are washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 30% Hep EtOAc in Hep) to yield 1-24 (1 , 1 g, 84%) m / z 506.1 [M + H].
    [00191] The following intermediates are prepared in a similar manner:
    Structure intermediate m / z go 1-26 AT k 1-26 AT
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    Structure Intermediate m / z _ f Q / A O ~ - <, ON X'-X. / ° kH / I-27 417.9 [M + H] οNTHE. 1-28 AT
    v ___j .......
    Method 10
    Synthesis of Intermediate 1-30
    [00192] A solution of N21 (260 mg, 0.52 mmol) in 1: 1 dioxane / water (8 mL) is treated with LiOH (120 mg, 5.0 mmol). The mixture is heated to reflux for 2 h, then the volatiles are removed in vacuo. The residue is acidified to pH = 4 with 2M aqueous HCI, extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue is dissolved in DMF (4 ml) and treated with pyridine (80 µL, 1.0 mmol) and Boc anhydride (80 mg, 1.0 mmol). The solution is stirred for 10 min, then ammonium bicarbonate (95 mg, 1.2 mmol) is added. The mixture is stirred
    81/118 before 16 h, then the volatiles are removed in vacuo. The residue is divided between EtOAc and saturated aqueous NH 4 CI. The organics are washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO 2 , 2080% EtOAc in Hep, then 20% MeOH in CH 2 CI 2 ) to yield 1-29 (180 mg, 75%) m / z 475.0 [M + HJ.
    [00193] In a stirred solution of I-29 (180 mg, 0.38 mmol) in CH 2 CI 2 (3 ml) is added TFA (2 ml). The solution is stirred at room temperature for 3 h, then the volatiles are removed in vacuo. The residue is divided between saturated aqueous NaHCO 3 and EtOAc. The organics are collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide 1-30 (130 mg, 92%) m / z 375.0 [M + H], [00194] The following intermediates were prepared similar way:
    Structure Intermediate m / z yO ob / H and NX / X / O Λ X / NH 1-31p X '' θQ) I-32
    82/118
    Structure Intermediate m / z 0 A Vv H 2 N — C o EN H 1-330 — ZOhM X = /ON'QrH 1-34„Çy °NH 1-35Ο — ζ P yh 2 n — C ON {T _- NH 1-36
    83/118
    Structure intermediate m / z oX o / 7 / h 2 nA> = / O NH a 1-37O — Z f O 1-38p X /ON 1-39
    Method 11
    Intermediate Summary 1-41
    [00195] In a solution of R-9 (5.00 g, 23.6 mmol) in THF (50 mL) is added to the 60% dispersion of sodium hydride in mineral oil (1.41 g, 35.1 mmol). The mixture is stirred for 5 min at
    84/118 room temperature, then diethyl carbonate (5.7 mL, 47.4 mmol). The reaction is stirred for 30 min at room temperature, then heated to reflux for 2 h. The mixture is cooled to room temperature, then divided between saturated aqueous NH 4 CI and EtOAc. The organics are collected and concentrated in vacuo to provide a residue that is purified by f / ash chromatography (SiOg, Hep 70% EtOAc in Hep) to yield 1-40 (6.2 g, 93%) m / z 285 , 1 [IVHHJ.
    [00196] In a cooled (0 ° C) solution of M0 (5.2 g, 18.3 mmol) in CH 2 CI 2 (46 ml.) SO 2 CI 2 (1.5 mL, 18.3 mmol). The mixture is allowed to warm to room temperature and stirred for 30 min, then treated with water, extracted with OH 2 CI 2 , dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide 1-41 (quant) m / z 318.9 [M + H],
    Method 12
    Summary of Intermediate I-43
    [00197] A solution of 1-15 (400 mg, 1.48 mmol) and 1-41 (943 mg, 2.96 mmol) in / -PrOH (15 mL) is treated with pyridine (0.36 mL, 4 , 44 mmol). The mixture is heated at 60 Q C for 3 days, then the volatiles are removed in vacuo. The residue is purified by flash chromatography (SiO 2 , 40% Hep EtOAc in Hep) to produce M2 (240 mg, 30%) m / z 535.2 [M * H].
    [00198] A solution of M2 (240 mg, 0.45 mmol) in MeOH (3
    85/118 ml), THF (1 ml) and 5M aqueous NaOH (0.5 ml) is heated to 60 ° C for 3 h. The mixture is cooled to room temperature, then acidified to pH ™ 1 with 6M aqueous HCI. The mixture is extracted with CH 2 CI 2 , then filtered through a phase separator®, then the volatiles are removed in vacuo. The residue is dissolved in DMF (2 ml) and treated with pyridine (324 mg, 4.1 mmoi), Boc anhydride (327 mg, 0.45 mmoi), followed by ammonium bicarbonate (215 mg, 2.72 mmol ). The mixture is stirred for 3 h, then the volatiles are removed in vacuo to provide a residue which is purified by flash chromatography (SiO 2 , CH 2 CI 2 to 5% MeOH in ÇH 2 CI 2 ). The purified material is dissolved in CH 2 CI 2 (5 ml) and treated with HÇ | at 4.0M in doxane (1.1 mL). The mixture is stirred for 1 h, then the volatiles are removed in vacuo to provide a residue, which is purified by flash chromatography (SiO 2 , CH 2 CI 2 to 20% MeOH in CH 2 CI 2 containing 2.5% TEA) to produce M3 (134 mg, 73%) m / z 405.9 [M + HJ.
    [00199] The following compounds are made in a similar way:
    Structure Intermediate m / z nh 2 íxn 0 « i-44 380.8 [M + H] NH to Ç% οχ '^ X 7 kX V-NH M5 380.4 [M + H]
    86/118
    [00200] In a solution of 1-14 (160 mg, 0.62 mmol) and M1 (298 mg, 0.94 mmol) in ÀPrOH (6.2 mL) is added pyridine (0.15 mL, 1.9 mmol). The solution is heated to 70 ° C for 24h, then the volatiles are removed in vacuo. The crude is purified by fes / Chromatography. (SiO 2 , Hep 40% EtOAc in Hep) to yield 1-46 (144 mg, 44%) m / z 521.2 [M + H], [00201] A solution of I-46 (144 mg, 0.28 mmol) in MeOH (2 mL) and 3M aqueous NaOH (2 mL) is heated to 65 ° C for 3 h, then cooled to room temperature. The solid is filtered, collected and dried, then dissolved in DMF (2 ml) and treated with TBTU (71 mg, 0.22 mmol). The mixture is stirred for 15 min, then treated with 7M ammonia in MeOH (7 ml). The mixture is stirred for 20 min, then the volatiles are removed in vacuo. The residue is divided between water and EtOAc, and the organics are collected and concentrated. The crude is purified by f / ash chromatography (Hep a
    87/118
    EtOAc). The resulting compound is dissolved in CH 2 CI 2 (2 ml) and treated with TFA (1 ml). The reaction mixture is stirred for 2 h, then the volatiles are removed in vacuo. The crude is divided between CH 2 CI 2 and 10% aqueous Na 2 CO 3 (w / w) and CH 2 C 1 2 . The organics are collected and filtered through a phase separator® to provide after removal of volatiles 1-47 (58 mg ; 53%) m / z 392.1 [M + H]. Method 14
    Synthesis of Intermediate 1-51
    [00202] A solution of I-20 (500 mg, 2.1 mmol) and media propriolate (0.35 mL, 4.1 mmol) in MeOH (10 mL) is heated to 65 ° C for 4 h. The mixture is concentrated in vacuo, then dissolved in diphenyl ether (2 ml) and heated at 200 ° C for 1 h. The mixture is cooled to room temperature, then purified by flash chromatography (SiO 2 , Hep to EtOAc) to yield M8 (317 mg, 50%) m / z 310.2 [M + HJ.
    [00203] In a solution of 1-48 (317 mg, 1.0 mmol) and p-TsOH Pyr (461 mg, 2.1 mmol) in CH 2 CI 2 (5 mL) is added NIS (461 mg, 2 , 1 mmol). The mixture is stirred in the dark at room temperature for 24 h. The mixture is treated with saturated aqueous Na 2 SO 3 , then filtered through a phase separator. The organics are collected
    88/118 and concentrated in vacuo to provide a residue, which is purified by flash chromatography (SiO 2: Hep to 80% EtOAc in Hep) to provide 1-49 (339 mg, 76%) m / z 436.0 [ M + H].
    [00204] The mixture of 1-49 (339 mg, 0.78 mmol), 4-phenoxyphenylboronic acid (333 mg, 1.56 mmol), and tetracis (triphenylphosphine) palladium (0) (90 mg, 0.078 mmol), and K 3 PO 4 (827 mg, 3.89 mmol) in dioxane (4 mL) is heated to 100 ° C in the microwave for 45 min. The mixture is cooled and concentrated in vacuo to provide a residue, which is purified by flash chromatography (SiO 2 , Hep to 80% EtOAc in Hep) to provide 1-50 (302 mg, 81%) m / z 478.2 [M + HJ.
    [00205] A solution of 1-50 (372 mg, 0.78 mmol) in MeOH (1.5 mL), THF (1 mL) and 3M aqueous NaOH (3 mL) is heated at room temperature for 20 h, then acidified to pH ~ 5 with concentrated aqueous HCI. The volatiles are removed in vacuo and the residue crushed with a mixture of CH 2 CI 2 and MTBE. The solid is filtered, collected and dried. The solid is dissolved in DMF (2 ml) and treated with pyridine (0.1 ml, 1.2 mmol), Boc anhydride (69 mg, 0.87 mmol), followed by ammonium bicarbonate (96 mg, 1, 2 mmol). The mixture is stirred for 16 h, then divided between water and CH2 Cl2 · The mixture is filtered through a phase separator® and the organics are concentrated in vacuo to provide a residue, which is purified by flash chromatography (SiO 2 , CH 2 CI 2 to 5% MeOH in CH 2 CI 2 ). The purified material is dissolved in CH 2 CI 2 (2 ml) and treated with 4.0 M HCI in dioxane (4 ml). The mixture is stirred for 2 h, then the volatiles are removed in vacuo to provide a residue, which is purified by trituration with MTBEiEtOAc to yield 1-51 (75 mg, 22%) m / z 393.1 [M + H ].
    [00206] The following intermediates are prepared in a similar way:
    89/118
    Structure Intermediate m / zÍ-52 403.2 [M + H] Method 15
    Summary of Intermediate 1-54
    t-53 [00207] In a solution of 1-9 (1.50 g, 5.4 mmol) in DMF (20 mL) is added sodium hydride (60% dispersion in mineral oil, 0.26 g, 6 , 5 mmol). The mixture is stirred for 5 min, then 1-1 (2.39 g, 6.5 mmol) is added. The mixture is heated to 70 ° C for 18 h, then cooled to room temperature. The mixture is divided between EtOAc and water, then the organics are collected, dried in Na 2 SO 4: filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO 2 , 70% Hep EtOAc in Hep) to provide I-53 (1.2 g, 47%) m / z 472.2 [M + HJ.
    [00208] A solution of I-53 (1.00 g, 2.2 mmol) in AcOH (5 mL) and concentrated aqueous HCI (1 mL) is heated to 90 ° C for 10 h. The mixture is cooled to room temperature, then poured into ice. The mixture is basified at pH 9 10 by the addition of ammonium hydroxide, then extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue is purified
    90/118 AD · by RHPLC to provide i-54 (0.39 g, 48%) m / z 390.1 [M + H], [00209] The following intermediates are prepared in a similar manner:
    Intermediate m / z GOC ~O" 1-54 378.1 [M + H] HONH, f: ./nandH 1-55 418.2 [M + H] * οί'θ 1-56/ H = V 7 ω-'ν * H 1-57 404.1 [M-í-H] NH,Q 1-58 404.1 [M + H]
    91/118
    Method 16
    Synthesis of Example 9
    [00211] In a solution of I-7 (2.00 g, 7.5 mmol) in DMF (20 mL) are added Cs 2 CO 3 (4.9 g, 15 mmol) and 1-3 (4.0 g, 11 mmol). The reaction mixture is heated to 60 ° C for 24 h, then cooled to room temperature. The mixture is partitioned between EtOAc and water. The organics are collected, washed with water, dried over MgSO 4 , filtered and concentrated in vacuo. The crude is purified by ffesh chromatography (SiO2, Hep 30% EtOAc in Hep) to provide I59 (2.10 g, 62%) m / z 445.0 [M + HJ.
    [00212] In a solution of 1-59 (7.00 g, 15.6 mmol) in 1: 1 dioxide: water (50 mL) is added LiOH (3.00 g, 125 mmol). The reaction mixture was heated to reflux for 2h, then the volatiles are removed in vacuo. The residue is acidified with 2N aqueous HCl at pH = 4, then diluted with EtOAc. washed with brine, dried on NâaSOzf, filtered and concentrated in vacuo. The residue is dissolved in DMF (30 mL) and treated with Boc anhydride (2.22 g, 28 mmol), followed by ammonium bicarbonate (2.21 g, 28 mmol) and pyridine (2.2 mL, 28 mmol) ). The mixture is stirred for 16 h, then the volatiles are removed in vacuo. The residue is divided between EtOAc
    92/118 and saturated aqueous NH 4 CI, then the organics are collected, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 20-80% EtOAc in Hep, then 20% MeOH in CH 2 CI 2 ) to provide 1-60 (3.8 g. 61%) m / z 421 , 0 [M + H].
    [00213] To a solution of pine benzol 4benzylphenylboronic acid ester (47 mg, 0.16 mmol) in DME (1 mL) is added a solution of 1-19 (45 mg, 0.11 mmol) in DME (1 mL) . To this solution is added aqueous 1 M K 2 CO 3 (1 ml) and SiliaCat DPP-Pd (50 mg, 0.01 mmol). The mixture is heated at 100 ° C for 16 h, then concentrated in vacuo. The crude was purified by RHPLC to provide a residue, which is dissolved in DCE and treated with 4.0M HCI in dioxane (0.5 ml). The mixture is stirred for 16 h, then the volatiles are removed in vacuo. To the residue is added a solution of acrylic acid (7.7 mg, 0.11 mmol), EDC (23 mg, 0.12 mmol), and DIEA (35 µL, 0.20 mmol) in DMA (0.8 mL ). The reaction mixture is stirred for 4 h, then the volatiles were removed in vacuo to provide a residue which was purified by RHPLC to provide example 9 (12 mg, 26%).
    [00214] The following compounds were prepared in a similar manner: Examples 1-8,10-27, 94-96 Method 17
    Synthesis of Example 28
    Ex 28
    93/118 [00215] In a solution of 1-30 (75 mg, 0; 20 mmol) in DMF (2 mL) is added DIEA (0.3 mL), TBTU (96 mg, 0.30 mmol) and acrylic (22 mg, 0.30 mmol). The mixture is stirred for 12 h at room temperature, then treated with water. The mixture is extracted with EtOAc, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (30 to 90% EtOAc in Hep) to produce example 28 (36 mg, 42%).
    [00216] The following compounds are prepared in a similar manner: Examples 29, 33, 39, 42, 45.47, 55, 88
    Method 18
    Synthesis of Example 38
    L32
    Ex38 [00217] In a solution of 1-32 (70 mg, 0.18 mmol) in DMF (3 mL) are added DIEA (1 mL), TBTU (116 mg, 0.36 mmol) and R-10 (17 mg, 0.20 mmol). The mixture is stirred for 12 h at room temperature, then treated with water. The mixture is extracted with EtOAc, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by RHPLC to produce example 38 (38 mg, 46%).
    [00218] The following compounds are prepared in a similar manner: Examples 31, 32, 43, 48, 49, 56
    Method 19
    Synthesis of Example 37
    94/118
    [00219] In a solution of I-32 (25 mg, 0.064 mmol) in DMF (2 mL) are added DIEA (0.4 mL), TBTU (32 mg, 0.080 mmol) and R11 (10 mg, 0.080 mmol) . The mixture is stirred for 12 h at room temperature, then treated with water. The mixture is extracted with EtOAc, dried over Na2SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 30 to 70% EtOAc in Hep) to produce example 37 (5 mg, 16%).
    [00220] The following compounds are prepared in a similar manner: Examples 30, 36
    Method 20
    Synthesis of Example 40
    J-32
    Ex40 [00221] In a solution of 1-32 (100 mg, 0.26 mmol) in CH 2 C1 2 (2 mL) is added EDO (60 mg, 0.31 mmol) followed by acrylic acid (22 mg, 0 , 31 mmol). The mixture is stirred at room temperature for 1 h, then directly purified by flash chromatography (SiO 2 , CH 2 CI 2 at 5% MeOH in CH 2 CI 2 ) to produce example 40 (15 mg, 13%).
    [00222] The following compounds were made in a similar way: Examples 86, 8S (R-10 used in the treatment of acrylic acid)
    95/118
    Method 21.
    Synthesis of Example 60
    Oa.üM MCI roí d! O> »on } SOC. CicA. an. acrj'ifcai.-W
    Acrylic acid [00223] In a solution of 1-60 (43 mg, 0.10 mmol) in DME (2 mL) is added R-12 (65 mg, 0.18 mmol), SiliaCat DPP-Pd (50 mg, 0.01 mmol) and potassium carbonate (500 mg). The mixture is heated to 140 ° C in a microwave for 2 h, then concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 0 to 4% MeOH in CH 2 CI 2 ) to yield 1-61 (38 mg, 72%) m / z 519.2 [M + H].
    [00224] 1-61 (38 mg, 0.073 mmol) is dissolved in CH 2 CI 2 (2 ml) and treated with 4.0 M HCl in dioxane (3 ml). The mixture is stirred for 2 h at room temperature, then the volatiles are removed in vacuo. The residue is dissolved in CH 2 CI 2 (2 ml) and treated with acrylic acid (5 mg, 0.073 mmol) and EDC (14 mg, 0.073 mmol). The mixture is stirred for 1 h at room temperature, then divided between water and CH 2 CI 2 . The mixture is filtered through a phase separator®, and the organics are collected and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2, CH 2 Cl 2 to 8% MeOH in CH 2 CI 2) to afford Example 60 (13 mg, 57%).
    [00225] The following compounds were made in a similar manner: Example 61 Method 22
    96/118
    Synthesis of Example 72
    [00226] One flask is loaded with 1-60 (4.0 g, 9.5 mmoi), 4-hydroxyphenylboronic acid (1.9 g, 14 mmoi), bis (di-tam-butií (4-dimethylminophenyl) phosphine) dicioropaiádío (ll ) (0.67 g, 0.95 ml), potassium carbonate (2.5 g, 18 ml) and treated with DMF (40 ml) and water (10 ml). The mixture is heated in the microwave at 140 ° C for 90 min. The mixture is cooled to room temperature, then treated with saturated aqueous NH4 Cl, extracted with EtOAc, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2> 20 to 50% EtOAc in Hep) to yield 1-62 (2.0 g, 54%) m / z [M + H], [00227] In a solution of 1- 62 (90 mg, 0.23 mmoi) in CH 2 CI 2 (7 ml) is added 3-tolylboronic acid (95 mg, 0.70 mmoi), Cu (Oac) 2 (300 mg), pyridine (1 ml) , TEA (1 mL) and molecular sieves (4A). The mixture is stirred at room temperature outdoors for 12 h. The mixture was filtered through a silica gel pad and the volatiles of the filtrate are removed in vacuo. The crude is purified by RHPLC to provide 1-63 (61 mg, 55%) m / z 477.1 [M + H].
    [00228] In a solution of 1-63 (55 mg, 0.115 ml) in CH 2 CI 2 (3 ml) is added TEA (1 ml). The mixture is stirred at room temperature for 2 h, then treated with saturated aqueous Na 2 CO 3 . The layers are separated, and the volatiles of the organics are re
    97/118 moved in a vacuum to provide a residue. The residue is dissolved in DMF (4 ml) and treated with acrylic acid (0.6 ml) and EDC (38 mg, 0.25 mmol). The mixture is stirred at room temperature for 12 h and then directly purified by RHPLC to produce example 72 (17 mg, 34%).
    [00229] The following compounds are prepared in a similar manner: Examples 62-71, 73-76
    Method 23
    Synthesis of Example 90
    [00230] In a solution of i-31 (0.20 g, 0.55 mmol) in DMA (3 mL) are added DIEA (0.15 mL, 0.86 mmol) and R-13 (0.12 g , 0.71 mmol). The mixture is heated at 50 C ° C for 18 h, then cooled to room temperature. The mixture is divided between water and EtOAc. The organics are collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by RHPLC to provide I64 (0.15 g, 62%) m / z 447.1 [M + H], [00231] in a solution of 1-64 (70 mg, 0.16 mmoi) in DMF (2 mL) TBTU (60 mg, 0.19 mmol) and DIEA (0.06 mL, 0.19 mmol) are added. The mixture is stirred for 5 min, then treated with a 2.0M solution of methylamine in THF (0.24 ml, 0.47 mmol). The mixture is stirred at room temperature for 16 h, then treated with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc, dried over Na 2 SO 4 . filtered and concentrated in vacuo. O
    98/118 crude is purified by RHPLC to provide example 90 (7 mg, 10%),
    Method 24
    Synthesis of Example 93
    [00232] In a solution of 1-31 (100 mg, 0.28 mmol) in CH 2 CI 2 (5 mL) TBTU (91 mg, 0.28 mmol) and R-14 (prepared according to J Chem. 2001, 44, 2719-2734, 70 mg, 0.41 mmol). The mixture is stirred at room temperature overnight, then filtered and purified by flash chromatography (SiO 2 , CH 2 CI 2 to 10% MeOH with 1% ammonium hydroxide) to produce example 93 (58 mg, 41 %).
    Method 25
    Synthesis of Example 58
    Exsa [00233] In a solution of i-47 (29 mg, 0.074 mmol) in CH 5 CI 2 (2 mL) EDC (92 mg, 0.38 mmol) and R-10 (20 mg, 0.24) are added mmol). The mixture is stirred at room temperature for 1h, then divided between water and CH 2 CI 2 . The mixture is filtered through a phase separator®, and the organics are collected and concentrated
    99/118 in a vacuum. The crude is purified by flash chromatography (SiO 2 , 20 to 100% EtOAc in Hep) to produce example 58 (23 mg, 68%).
    [00234] The following compounds are made in a similar way:
    Examples 78, 85, 52, 53
    Method 26
    Summary of Example 79
    M3
    Bx79 [00235] In a solution of 1-43 (65 mg, 0.16 mmol) in CH 2 CI 2 (2 mL) is added EDO (37 mg, 0.19 mmol) followed by acrylic acid (14 mg, 0 , 19 mmol). The mixture is stirred at room temperature for 1 h, then directly purified by flash chromatography (SiO 2 , CH 2 CI 2 at 5% MeOH in CH 2 CI 2 ) to produce example 79 (14 mg, 19%).
    [00236] The following compounds were made in a similar way: Examples 34,50,51, 57,84
    Method 27
    Synthesis of Example 77
    [00237] A solution of morpholine (35 mg, 0.4 mmol), acid (E) -4
    100/118 bromo-but-2-enoic (79 mg, 0.48 mmol) and Hunig's base (0.21 ml, 1.2 mmol) in DMF (2 ml) is stirred for 18 h. EDC (71 mg, 0.37 mlm) is added to this mixture. The mixture is stirred for 5 min, then treated with 1-54 (120 mg, 0.31 mmol) and stirred for 18 h. Saturated aqueous ammonium chloride is added (4 ml) and the mixture is extracted with EtOAc, dried over sodium sulfate, concentrated, and then purified by preparative TLC (SiO 2: 30% MeOH in EtOAc) to provide example 77 (64 mg, 38%).
    [00238] The following compounds are made in a similar way: Examples 98-100
    Method 28
    Synthesis of Example 80
    ÊXStí [00239] A solution of I-57 (200 mg, 0.51 mmol) in DMF (2 mL) is treated with DIEA (150 mg, 1.1 mmol), EDC (130 mg, 0.67 mmol), followed by acrylic acid (0.05 mL, 0.67 mmol). The solution is stirred for 16 h, then treated with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , EtOAc 10% MeOH in EtOAc) to provide example 80 (52 mg, 23%).
    [00240] The following compounds are prepared in a similar manner: Examples 35, 44, 54, 81, 82
    Method 29
    Synthesis of Example 41
    101/118
    [00241] In a solution of ί-53 (100 mg, 0.26 mmol) in DMF (2 mL) EDC (54 mg, 0.28 mmol) and R-10 (23 mg, 0.28 mmol) are added . The mixture is stirred at room temperature for 16 h, then divided between saturated aqueous ammonium chloride and EtOAc. The organics are collected, dried in Na 2 SO 4s filtered and concentrated. The crude is purified by flash chromatography (SiO 2 , EtOAc 10% MeOH in EtOAc) to produce example 41 (24 mg, 21%).
    [00242] The following compounds are prepared in a similar manner: Examples 83.91, 92
    Method 30
    Synthesis of Example 87
    [00243] In a solution of the 1-51 bis HCI salt (55 mg, 0.12 mmol) in CH 2 CI 2 (1.7 mL) are added TEA (29 mg, 0.29 mmol), EDC ( 34 mg, 0.17 mmol) and R-10 (15 mg, 0.17 mmol). The mixture is stirred at room temperature for 2 h, then divided between water and CH 2 CI 2 , then filtered through a phase separator®. The organics are collected and concentrated in vacuo to provide a residue, which is purified by flash chromatography (SiO 2 , CH 2 CI 2
    102/118 at 45% MeOH in CH 2 CI 2 ) to provide example 87 (25 mg, 46%).
    [00244] The following compounds were prepared in a similar manner:
    Examples 59, 46 (acrylic acid used in place of R-10)
    Method 31
    Synthesis of Example 97
    [00245] In a suspension of NaH (60% dispersion in mineral oil, 160 mg, 4.0 mmol) in DMF (5 mL) 1-9 (0.93 g, 3.35 mmol) is added. After 5 min of stirring, a solution of 1-67 (1.28 g, 3.35 mmol) in DMF (5 mL) is added. The mixture is heated to 70 ° C overnight, then cooled to room temperature and partitioned between EtOAc and water. The organics are collected and washed with water and brine, dried and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 0-70% EtOAc in Heptane) to provide 1-68 (0.59 g, 37%) m / z 486.7 [M + H], [00246] 1 -68 (0.59 g, 1.22 mmol) is diluted with EtOH (1 mL) and water (0.5 mL) and hydroxide (dimethylphosphinite-kP) [latinum (Π) hydrogen (Π) ( 0.07 g, 0.163 mmol) is added. THE
    103/118 The mixture is heated to 80 ° C overnight, then concentrated in vacuo. The residue is dissolved in ΟΗ 2 Οί 2 , then filtered and concentrated to provide 1-69 (0.28 g, 45%) m / z 504.7 [M + H].
    [0Q247] i-69 (50 mg, 0.1 mmol) is dissolved in CH 2 CI 2 (0.8 mL) and
    TFA (0.08 ml). The mixture is stirred for 3 h, then divided between CH 2 ÇI 2 and aqueous saturated NaHCO 3 . The organics are combined and concentrated to produce a residue that is treated with a pre-stirred solution (15 min) of acrylic acid (10 μl, 0.13 mmol), EDO (3.5 mg, 0.18 mmol) and base from Hunig (70 µL, 0.38 mmol) in DMF (1.0 mL). The mixture is stirred overnight, then diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics are combined, washed with brine, dried over Na 2 SO4, filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 ) to provide example 97 (5 mg, 88%).
    Method 32
    Summary of Example 101
    [00248] In a solution of 3-amino ~ 4-cyanopyrazole (100 g, 0.9 mol) in DMF (1 L) NBS (197.5 g, 1.1 mol) is added, and the mixture is stirred for 10 h at room temperature. The mixture is concentrated in vacuo, then dissolved in EtOAc and washed with brine (8 x). The organics are collected and concentrated in vacuo to propose
    104/118 cíonar ί-70 (50 g, 29%) m / z 187.0 [M + J.
    [00249] A vial is loaded with 1-70 (1.0 g, 5.35 mmol), 2-phenoxy-5- (4,4,5,5-tetramefil- [1,3,2] dioxaborolan-2-yl ) -pyridine (2.07 g, 6.95 mmol), tetrads (triphenylphosphine) palladium (0) (0.62 g, 0.535 mmol) and dissolved in aqueous potassium carbonate (10 mL, 2.0 M) and DME (6 mL). The mixture is heated at 130 ° C for 3 h in a microwave. The mixture is filtered, then diluted with water, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO 2 , 0-100% EtOAc in heptanes) to produce 1 * 71 (1.18 g, 80%) m / z 278.0 [M + H].
    [00250] Sodium hydride (60% dispersion in mineral oil, 100 mg, 2.5 mmol) is added to the solution of 1-71 (530 mg, 1.9 mmol) in DMF (7.5 mL). The mixture is stirred for 5 min, then treated with 1-1 (840 mg, 2.3 mmol) and heated to 70 ° C for 18 h. The solution is cooled to room temperature, then divided between EtOAc and water. The organics are collected, dried, filtered and concentrated in vacuo to provide a residue, which is purified by flash chromatography (SiO 2> 0-100% EtOAc in heptanes) to produce I-72 (310 mg, 35%) m / z 473.2. [M + H].
    [00251] 1-72 (0.31 g, 0.66 mmol) is diluted with EtOH (5 mL) and water (0.5 mL) and Hydride (kP dimethylphosphinous acid) [hydrogen bis (dimethylphosphinite-kP)] platinum (II) (28 mg, 0.066 mmol) is added. The mixture is heated to 80 ° C overnight, then concentrated in vacuo. The residue is dissolved in CH 2 CI 2 , then filtered and concentrated to provide a residue which is dissolved in TFA (5 ml) and stirred for 3 h at room temperature, then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agilent Stratospheres PL-HCO3 MP SPE cartridge and concentrated in vacuo to provide I-73 (0.25 g, 98%) m / z 391.2 [M + HJ.
    105/118 [00252] 1-73 (110 mg, 0.28 mmol) is treated with a pre-agitated solution (15 min) of acrylic acid (21 pL, 0.13 ml) and EDO (65 mg, 0.34 ml) ) in DMF (2.0 ml). The mixture is stirred overnight, then diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics are combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO 2 , 10% MeOH in EtOAc) to provide example 101 (32 mg, 26%).
    [00253] The following compounds are made in a similar way: Examples 102-103,110
    Method 33
    Synthesis of Example 122
    P7Õ
    [00254] In a solution of 1-71 (1.1 g, 3.97 mmol) in DMF (20 mL) is added NaH (60% dispersion in mineral oil, 190 mg, 4.76 mmol). The mixture is stirred for 5 min, then treated with 1-4 (1.82 g, 4.76 ml) and heated to 70 ° C for 18 h. The mixture is cooled, then divided between EtOAc and water. The organics are collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo to produce a residue, which is purified by flash chromatography.
    106/118 (SiO 2 , 0-80% EtOAc in heptanes) to yield 1-74 (520 mg, 27%) m / z 487.3 [M + HJ and 1-75 (500 mg, 26%) m / z 487.3 (M + HJ.
    [00255] 1-74 (250 mg, 0.514 mmol) is diluted with EtOH (5 ml) and water (0.5 ml.) And Hydride (kP dimethylphosphinous acid) [hydrogen bis (dimethylphosfinite-kP)] platinum (11) (22 mg, 0.051 mmol) is added. The mixture is heated to 80 L C overnight, then concentrated in vacuo. The residue is dissolved in CH 2 CI 2; then filtered and concentrated to provide a residue, which is dissolved in TFA (5 ml) and stirred for 3 h at room temperature, then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agilent Stratospheres PL-HCO3 MP SPE cartridge and concentrated in vacuo to provide I-76 (0.206 g, 98%) m / z 405.3 [M + H], [00256] 1-76 (254 mg, 0.63 mmol) is treated with a pre-agitated solution (15 min) of R-10 (69 mg, 0.82 mmol) and EDO (144 mg, 0.75 mmol) in DMF (2 , 0 ml). The mixture is stirred overnight, then diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics are combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography (SIO 2 , 10% MeOH in EtOAc) to provide example 122 (48 mg, 16%).
    [00257] The following compounds are made in a similar manner: Examples 114,117-120,123,150-152 Method 34
    Synthesis of Example 104
    107/118
    [00258] A vial is loaded with 8-70 (0.50 g, 2.67 mmol), 4-isopropoxyboronic acid (0.58 g, 3.21 mmol), tetracis (triphenylphosphine) palladium (0) (0, 43 g, 0.37 mmol) and dissolved in aqueous potassium carbonate (4 ml, 2.0 M) and DME (3 ml). The mixture is heated at 130 ° C for 3 h in a microwave. The mixture is filtered, then diluted with water, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO 2 , 0-80% EtOAc in heptanes) to yield 1-77 (0.473 g, 73%) m / z 243.5 [M + H].
    [00259] Sodium hydride (60% dispersion in mineral oil, 55 mg, 1.37 mmol) is added to the solution of 8-77 (300 mg, 1.24 mmol) in DMF (5 mL). The mixture is stirred for 5 min, then treated with 1-1 (550 mg, 1.47 mmol) and heated to 70 ° C for 18 h. The solution is cooled to room temperature, then divided between EtOAc and water. The organics are collected, dried, filtered and concentrated in vacuo to provide a residue, which is purified by flash chromatography (SíO 2 , 0-100% EtOAc in heptanes) to produce 8-78 (200 mg, 37%) m / z 438.6 [M + H], [00260] 1-78 (190 mg, 0.43 mmol) is diluted with EtOH (4 mL) and water (2 mL) and Hydride (kP dimethylphosphinous acid) [hydrogen
    108/118 bís (dimethylphosphine-RP)] platinum (II) (11 mg, 0.026 mmol) is added. The mixture is heated to 80 ° C overnight, then concentrated in vacuo. The residue is dissolved in CH 2 CI 2 , then filtered and concentrated to provide a residue, which is dissolved in CH 2 Ci 2 (5 ml) and TFA (1 ml) and stirred overnight at room temperature, then concentrated in a vacuum. The residue is dissolved in MeOH and passed through an Agilent Stratospheres PL-HCO3 MP SPE cartridge and concentrated in vacuo to provide I-79 (110 mg, 71%).
    [00261] 1-79 (40 mg, 0.11 mmol) and acrylic acid (10 mg, 0.14 mmol) in DMF (5 mL) are treated with HATU (88 mg, 0.17 mmol) and Hunig's base (60 pL, 0.34 mmol) in DMF (2.0 mL). The mixture is stirred overnight, then concentrated in vacuo. The crude is purified by RHPLC to provide example 105 (25 mg, 54%).
    [00262] The following compounds are made in a similar manner: Examples 104, 106-109, Τ11-113, 115-116, 124, 133 s 134-136, 138139,141-144,147-149,166 Method 35
    [00253] A vial is loaded with 1-70 (0.45 g, 2.41 mmol),
    109/118 4-n-propoxyboronic acid (0.48 g, 2.65 mmol), tetracis (triphenylphosphine) palladium (0) (0.28 g, 0.24 mmol) and dissolved in aqueous potassium carbonate (4, 8 ml, 2.0 M) and dioxane (2 ml). The mixture is heated to 13 0 C overnight. The mixture is filtered, then diluted with water, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO 2j 0-6% MeOH in CH 2 CI 2 ) to yield 1-80 (0.400 g, 69%) m / z 242.4 [M +].
    [00264J Sodium hydride (60% dispersion in mineral oil, 33 mg, 0.82 mmol) is added to the solution of 1-80 (200 mg, 0.74 mmol) in DMF (5 mL). The mixture is stirred for 5 min, then treated with 1-6 (318 mg, 0.82 mmol) and heated to 70 ° C for 18 h. The mixture is concentrated in vacuo and purified by flash chromatography (SiO 2 , 35% EtOAc in heptanes) to yield 1-81 (130 mg, 39%) m / z 452.9 [M + H], [00265] 1 -81 (130 mg, 0.29 mmol) is diluted with EtOH (1.5 mL) and water (0.5 mL) and hydroxide (dimethylphosphonic acid kP) [hydrogen bis (dimethylphosphite-kP) j platinum (II ) (13 mg, 0.029 ml) is added. The mixture is heated to 80 ° C overnight, then concentrated in vacuo. The residue is dissolved in EtOAc, then filtered and concentrated to provide a residue which is dissolved in CH 2 CI 2 (1 ml) and TFA (1 ml) and stirred for 1 h at room temperature, then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agilent Stratospheres PL-HCO3 MP SPE cartridge and concentrated in vacuo to provide i-82 (80 mg, 84%).
    [00266] I-82 (130 mg, 0.35 mmol) is treated with a pre-agitated solution (15 min) of acrylic acid (30 mg, 0.42 mmol) and EDO (81 mg, 0.42 mmol) in DMF (2.0 mL). The mixture is stirred overnight, then diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics are combined, dried over Na 2 SO 4 , fil
    110/118 irate and concentrated in vacuo. The crude is purified by RHPLC to provide example 125 (30 mg, 20%).
    [00267] The following compounds are made in a similar way:
    Examples 130,132,145-146, 153, 155-156,159,162-163, 165
    Method 36
    Synthesis of Example 126
    [00268] Sodium hydride (60% dispersion in mineral oil, 80 mg, 2.02 mmol) is added to a solution of 1-80 (445 mg, 1.84 mmol) in DMF (5 mL). The mixture is stirred for 5 min, then treated with 1-4 (770 mg, 2.02 mmol) and heated to 70 ° C for 18 h. The mixture is diluted with saturated aqueous ammonium chloride, extracted with EtOAc, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO 2 , 0- 6% MeOH in CH 2 CI 2 ) to yield 1-81 (200 mg, 24%) and I-84 (300 mg, 36%) m / z 452 , 5 [M + H].
    [00269] 1-84 (300 mg, 0.66 mmol) is diluted with EtOH (1.5 ml) and water (0.5 ml) and hydroxide (kP dimethylphosphinous acid) [hydrogen bis (dimethylphosfinite-kP)] platinum (II) (28 mg, 0.066 mmol) is added. The mixture is heated to 80 ° C for 72 h, then concentrated in vacuo. The residue is dissolved in EtOAc, then filtered and
    111/118 centered to provide a residue, which is dissolved in CH2 Cl2 (1 ml) and TFA (1 ml.) And stirred for 1 h at room temperature, then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agilent Stratospheres PL-HCO3 MP SPE cartridge and concentrated in vacuo to provide I-85 (270 mg).
    [00270]! -85 (80 mg, 0.22 mmol) is treated with a pre-agitated solution (15 min) of acrylic acid (19 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol) in DMF (2.0 mL). The mixture is stirred overnight, then diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics are combined, dried in Na-SOz ;, filtered and concentrated in vacuo. The crude is purified by RHPLC to provide example 126 (7 mg, 8%).
    [00271] The following compounds are made in a similar way: Examples 131
    Method 37
    Synthesis of Example 140
    Ex 140 [00272] 1-82 (80 mg, 0.22 mmol) is treated with a pre-agitated solution (15 min) of R-10 (24 mg, 0.28 mmol) and EDO (50 mg, 0.26 mmol) ) in DMF (2.0 ml). The mixture is stirred overnight, then diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics are combined, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by RHPLC to provide example 140 (14 mg, 15%).
    112/118 [00273] The following compounds are made in a similar way:
    Example 128,137,154,157-158,160-161,164,167-168
    Method 38
    Synthesis of Example 127
    H! -85
    Ex's 27 [00274] I-85 (70 mg, 0.19 mmol) is treated with a pre-agitated solution (15 min) of R-10 (21 mg, 0.25 mmol) and EDO (44 mg, 0.23 mmol) ) in DMF (2.0 mL). The mixture is stirred overnight, then diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics are combined, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude is purified by RHPLC to provide example 127 (13 mg, 16%).
    [00275] The following compounds are made in a similar way: Example 129
    DESCRIPTION OF BIOLOGICAL PROPERTIES
    BTK Assay [00276] An HTRF assay (Cisbio KinEASE-TK cat # 62TK0PEC) was performed to quantify the ability of the test compounds to inhibit BTK-mediated phosphorylation of the substrate. The assays were grouped in 384-well plates, where 6nM of BTK labeled by human-sized human (Life Technologies cat # PV3587) and the test compound in varying concentrations were pre-incubated for 15 minutes at 28 ° C. Then 1 µM of TK-biotin substrate and 30 µM of ATP were added and incubated for an additional
    113/118 30 minutes at 28 ° C. Phosphorylation was detected by adding 62.5πΜ of Streptavidin-XL665 and TK Antibody Cryptate diluted 1: 100 in HTRF detection buffer (Cisbio cat # 62SDBRDF) and incubated for 60 minutes in RT. The plate was read in an Envision plate reader and the fluorescence is measured at 620nm (cryptate) and 665nm (XL665). A ratio is calculated (665/620) and converted to POC in relation to the control and absolute cavities.
    Test buffer:
    [00277] 50mM HEPES (Invitrogen # 15630), 0.01% Brij-35 (sigma # B4184), 10 mM MgCl 2 (Sigma M1028), 1mM EGTA (Ambion AM9262) and 100uM sodium orthovanadate ( Sigma S6508), 1 mM DTT (Sigma 05545) and 10 nM supplemental enzyme buffer (Cisbio caí # 61SEBALB).
    [00278] Preferred compounds for the treatment of autoimmune disorders exhibit selective BTK inhibition over other kinases such as EGFR. The compounds described here show a range of selectivities over EGFR when measured in cell assays (BTK activity measured by CD69 expression in primary CD19 + cells; EGFR activity measured by EGFR phosphorylation in A431 cells). See Table II.
    TABLE II
    Example IC50 B cell CD63 (nM) A431p-EGFR IC 50 (nM) 54 1.2 6.6 46 2.0 120 161 2.1 400 164 1.5 420 41 1 430 81 0.9 790 16 © 4.5 1200 78 2.5 1800 165 10 3700
    T14 / 118
    Example CD69 B cell ICso (nM) A431p-EGFR IC50 (nM) 107 8.2 4200 28 9 4700 103 15 5200 112 41 5800 113 24 6300 115 7.8 6400 40 20 > 10000 100 30 > 10000 158 58 > 10000
    Ό0279] Inhibition of B cell activation measured by CD69 expression [00280] Primary CD 19 + cells were purified from healthy frozen peripheral blood mononuclear cells (AlíCells, Emeryville, CA) and negatively selected by magnetic separation,> 97% of purity (Stemcell Technologies, Vancouver, CA). The cells were collected and seeded in a flat 96 base plate at a concentration of 2x1 oAcavity in RPMI media containing 10% FBS, rested for 1 hour at 37 ° C. The cells were treated with duplicate inhibitor or vehicle control at 1% final DMSO concentration for 1 hour at 37 ° C, 5% CO2. The cells were then stimulated with 12.5 µg / ml of Goat F (ab ! ) 2 anti-human IgD (SouthernBiotech, Birmingham, AL) for 18-24 hours at 37 ° C, 5% CO 2 . The cells were collected and stained for APC-CD19, clone HIB19 and PE-CD69, clone FN5Q (antibodies acquired from BD Bioscence, San Jose, CA). B cells were analyzed by flow cytometry using a BD LSRH or BD FACsCanto Flow Cytometer. Viable cells were monitored, and the percentage of CD69 was determined using the FlowJo software. inhibition of EGFR autophosphorylation in human A431 epithelial cells stimulated with epithelial growth factor
    115/118 [00281] A431 cells (Al CC # CR.L-1555 FZ) are thawed and seeded in DMEM containing 10% FBS in a 384 well treated tissue culture plate in 15,000 cells / well. After incubation for 24 hours at 37 ° C, 5% CO 2 , cells are treated with test compound (1% final DMSO concentration) and incubated for 16 hours at 37 ° C, 5% CO 2 . EGF (Millipore, 01-107) is added at a final concentration of 60 ng / mL and incubated for 10 minutes. The medium is removed, the cells are lysed, and EGFR phospho is measured (Meso Scale Diagnostics, N31CB-1).
    Therapeutic Use [00282] Based on their biological properties, the compounds of formula (I) according to the invention, or their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts in the aforementioned ways are adapted to treat disorders autoimmune and allergic due to the fact that they exhibit good inhibitory effect on BTK.
    [00283] Such diseases include, for example: rheumatoid arthritis, systemic entematous lupus, scleroderma. asthma, allergic rhinitis, allergic eczema, B cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing sponditis and uveitis.
    [00284] The compounds of formula (I) can be used alone or in combination with other active substances according to the invention, optionally in the same way in combination with other pharmacologically active substances.
    [00285] Suitable preparations include, for example, tablets, capsules, suppositories, solutions - particularly solutions for injection (s.c., Lv „i.m;) and infusion - elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound (s) must be
    116/118 is in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the composition as a whole, that is, in amounts that are sufficient to obtain the specific dosage range below. Specific doses can, if necessary, be given several times a day. [00286] Suitable tablets can be obtained, for example, by mixing the active substance (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as such as corn starch or alginic acid such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for delayed release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can likewise comprise several layers.
    [00287] Coated tablets can therefore be prepared by coating the cores produced analogously to the tablets with substances normally used for tablet coatings, for example, collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core can likewise consist of several layers. Similarly, the tablet coating may consist of several layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
    [00288] Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer, for example, flavoring such as vanillin or orange extract . They can likewise contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example,
    117/118 condensation of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
    [00289] Solutions for injection and infusion are prepared in the usual way, for example, with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and / or dispersant, while if water is used as the diluent, for example, organic solvents can optionally be used as solvating agents or dissolution aids, and transferred in injection vials or ampoules or infusion bottles.
    [00290] Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert vehicles such as lactose or sorbitol and packed in gelatin capsules.
    [00291] Suitable suppositories can be made, for example, by mixing with vehicles provided for this purpose such as neutral fats or polyethylene glycols or derived from them.
    [00292] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (for example, petroleum fractions), vegetable oils (for example, peanut or sesame oil), mono or polyfunctional alcohols ( eg ethanol or glycerol), vehicles such as, for example, natural mineral powders (for example, kaolin, clays, talc, chalk), synthetic mineral powders (for example, highly dispersed sialic acid and silicates), sugars (for example, sugarcane, lactose and glucose), emulsifiers (eg lignin, spent sulphite liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).
    [00293] The preparations are administered by the usual methods,
    118/118 preferably by oral or transdermal routine, more preferably by oral routine. For oral administration, the tablets may, of course, contain, in addition to the vehicles mentioned above, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used at the same time for the tablet manufacturing process. In the case of the aqueous suspension, the active substances can be combined with various flavor enhancers or dyes in addition to the excipients mentioned above.
    [00294] For parenteral use, solutions of the active substances with liquid vehicles can be used.
    [00295] The dosage for intravenous use is 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour.
    [00296] However, it may sometimes be necessary to deviate specified quantities, depending on body weight, the routine of administration, the individual response to the drug, the nature of its formulation and the time or interval in which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, while the upper limit may have to be exceeded. When administering large quantities, it may be advisable to debit them in several smaller doses distributed throughout the day, [00297] All patent and non-patent documents or literature cited in this application are hereby incorporated by reference in their entirety.
    权利要求:
    Claims (35)
    [1]
    1. Compound of formula (I)

    characterized by the fact that

    R t is N (R 3 ) 2 or hydrogen;
    Cy is aryl or heteroaryl each of which is replaced by R 2 and optionally substituted by halogen, halo Cm alkyl, Ci.4 alkyl and C M alkoxy;
    R 2 is chosen from:
    L-Ar, C1.6 alkyl and C · ^ alkoxy, each Ar, Ci. 6 alkyl and Ct. s alkoxy is optionally substituted by halogen, halo C M alkyl, C M alkyl, R 3 -S (O) nr , -CN, -C (O) -N (R 3 ) 2 or ^ .. 4 alkoxy;
    L is a linker chosen from a link, O,> C (O), Λ- ~ O- (CH 2 ) n -, <R>, -N (R 3 ) - (CH 2 ) n -, - (CH 2 ) n -N (R 3 ) -, -C (Q) N (R 3 ) ~, -CfOANCRsXCHzV, -Ν (Η3) -Ο (Ο) -Ν (Κ 3 ) -, -N (R 3 ) -C (O) -, -S (O) m N (R 3 ) - and -N (R 3 ) -SiO) m -, where -CH 2 - in each L can have 1-2 hydrogens substituted by alkyl, said Ci. 3 alkyl po groups
    [2]
    2/35 may optionally cyclize to form a C 3 ring. 6 cyclicalk;
    Air is carbocycle. heterocyclyl or heteroanla;
    Xi is a linker chosen from a link, - (CH 2 ) n -;
    Y is chosen from C 7 -C w spirocycle optionally containing 0-1 nitrogen atom in the ring, a nitrogen containing mono- or bicyclic heterocycle, carbocycle, aryl, each replaced by an R 4 ;
    R 4 is

    each n is independently 1-4;
    each m is independently 0-2;
    each R 3 is independently chosen from hydrogen
    [3]
    3/35 or Ç M alkyl;
    each R§ is independently chosen from hydrogen, Cm alkyl, C M alkoxy, C M alkHC M alkoxy, - (CH 2 ) n- heterocyclic and heterocycle each heterocycle optionally substituted by halogen, OH and RrS (Ok; | each group defined above for Cy, 5'R R R 1 X and Y which can be partially or fully halogenated;
    or a pharmaceutically acceptable salt thereof.
    2. Compound according to claim 1, characterized by the fact that
    Ring A is:

    or a pharmaceutically acceptable salt thereof.
    3. Composed according to claim 2, characterized by the fact that
    Cy is phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl each of which is replaced by R 2 and optionally replaced by F, Cl or Ci.4 alkoxy;
    R 2 is chosen from:
    L ~ Ar and Ci. 3 alkoxy, each Ar and C-1..3 aoxy is optionally substituted by F, Cl, C w alkyl, R 3 -S (O) r , -CN, -C (O) -NH (R 3 ) and Ci. 3 alkoxy;
    L is a linker chosen from a bond, O,> C (O), -CH 2 x -O-CHs-, -NH-, -NH-CHs-, -CH 2 -NH-, -CÇO-NH -CHr. -NH-C (O) NH-eN (R 3 ) ~ S (O) m -;
    Ar is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazoiyl, indole, isoindolyl, benzofuraniia, benzimidazolyl, benzothi
    [4]
    4/35 azolyl, piperidinyl, piperazinyl or pyrrolidinyl or a pharmaceutically acceptable salt thereof.
    4. Compound according to claim 3, characterized by the fact that
    Cy is phenyl or pyridinyl, each of which is replaced by R 2 and optionally substituted by F, Cl or C- 2 alkoxy;
    R 2 is chosen from:
    L-Ar and alkoxy, each Ar and C V 3 alkoxy is optionally substituted by F, Cl, C M aiquíla, CH 3 -S (Ó) 2-, -CN, -C (O) -NH (R 3 ) and alkoxy;
    L is a linker chosen from a bond, O,> C (O), -CH 2 -, -O-CH 2 -, -NH-, -NH-CH 2 -, -CH 2 -NH-, - C (O) -NH-CH 2 -, -NH-C (O) NH-SN (R 3 > S (OM
    Ar is phenyl, pyridinyl, pyridazinyl, pirlmidinlla, pyrazine, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazoyl or piperidinyl, or a pharmaceutically acceptable salt thereof.
    [5]
    5. Compound according to claim 4, characterized by the fact that
    Cy is phenyl or pyridinyl, each of which is replaced by R 2 and optionally replaced by F, Cl or CX alkoxy;
    R 2 is chosen from:
    L-Ar and Ci .. 3 alkoxy, each Ar and alkoxy is optionally substituted by F, Cl, C M aiquíla, CH 3 -S (O) 2-, -CN, -C (O) -NH (CH 3 ) and Cf.2 alkoxy;
    L is a linker chosen from a bond, O,> C (O), -CH 2 -, -O-CH 2 -, -NH-, -NH ~ CH 2 -, -CH 2 -NH-, - C (O) -NH-CH 2 -, -NH-C (O) NH-eN (H) -S (O) 2 -;
    Ar is phenyl, pyridinyl, benzoxazolyl or piperidinyl or a pharmaceutically acceptable salt thereof.
    5/35
    [6]
    6. Compound according to claim 5, characterized by the fact that
    X-í is a linker chosen from an e - (CH 2 ) n - bond;
    ¥ is chosen from:
    a spirit chosen from

    a heterocycle chosen from piperidinyl and pyrrolidine;
    and phenyl each heterocycle or phenyl substituted by an R 4 ;
    R 4 is


    where R $ cannot be hydrogen
    9v omt Η l or each R 4 is optionally halogenated;
    each R 5 is independently chosen from hydrogen, C1-3 alkyl, halo C <„ 3 alkyl, alkylC ; _ 3 alkoxy, -CH 2 -heterocycle and heterocycle each heterocycle optionally substituted by F, Cl, OH and CH 3 -S (O) 2 - and each heterocycle chosen from pyrrolidine, piperidinyl, morpholinyl and 1,4-oxazepan, or a pharmaceutically acceptable salt thereof.
    [7]
    7. Compound according to claim 6, characterized by the fact that
    X-ι is a linker chosen from a bond and ~ (CH 2 ) n -;
    6/35
    Y is chosen from:
    a spiro-cycle chosen from

    a heterocycle chosen from píperidiníla and pyrrolidiniía;
    and phenyl each heterocycle or phenyl substituted by an R 4 ;
    R4 is

    each R 5 is independently chosen from hydrogen, CI_ aíquda 3, -CF 3, C · ^ alkyl - C ^ alkoxy, -CH2-heterocycle , and heterocycle each optionally substituted heterocycle , by F, Cl, OH and Ch! 3 -S (O) 2 and each heterocycle chosen from pyrrolidinyl, piperidine and 1,4oxazepan, or a pharmaceutically acceptable salt thereof.
    [8]
    8. Compound according to claim 1, characterized by the fact that



    7/35


    8/35


    or a pharmaceutically acceptable salt thereof.
    [9]
    9. Compound according to claim 8, characterized by the fact that
    X-Y =


    9/35

    or a pharmaceutically acceptable outlet thereof.
    [10]
    10. Compound according to claim 9, characterized by the fact that
    Ring A is:

    technically acceptable
    [11]
    11. Compound according to claim 9, characterized by the fact that
    Ring A is:
    10/35

    or a pharmaceutically acceptable salt thereof.
    [12]
    12. Compound according to claim 9, characterized by the fact that
    Ring A is:
    NH, / y
    The 7 '
    S ^ N or a pharmaceutically acceptable outlet thereof.
    [13]
    13. Compound according to claim 9, characterized by the fact that
    Ring A is:
    : h 2 n

    or a pharmaceutically acceptable salt thereof.
    [14]
    14. Compound according to claim 2, characterized by the fact that
    Bé
    Home;
    L is a linker chosen from a linkage, O, and -O (8H 2 ) r ; in is 1-3;
    11/35
    Air is carboded or heterodichl;
    [15]
    15. Composed according to claim 14, characterized by the fact that
    Ar is C 3 .5 cidoaiquila or tetra-hídrofuranila;
    π = 1.
    [16]
    16. Composed according to claim 15, characterized by the fact that
    L-Ar ê !


    [17]
    17. Composed according to claim 2, characterized by the fact that
    R 2 is:
    , -OCH 2 CH 3 , -OCH 2 CH 2 CH 31 -OCH 3 , -OCF 3 or -OCH 2 CF 3 .
    [18]
    18. Compound, characterized by the fact that it is chosen from:
    12/35

    13/35

    14/35

    15/35

    16/35

    17/35

    18/35

    [19]
    19/35

    [20]
    20/35

    [21]
    21/35

    [22]
    22/35

    [23]
    23/35

    [24]
    24/35

    [25]
    25/35

    or the pharmaceutically acceptable salts thereof.
    19. Compound, characterized by the fact that it is chosen from:

    [26]
    26/35

    [27]
    27/35

    [28]
    28/35

    [29]
    29/35

    [30]
    30/35

    [31]
    31/35

    [32]
    32/35

    [33]
    33/35

    [34]
    34/35

    [35]
    35/35

    or the pharmaceutically acceptable salts thereof.
    20. Pharmaceutical composition, characterized by the fact that it comprises a therapeutically effective amount of a compound, as defined in claim 1, or a pharmaceutically acceptable salt thereof.
    21. Method of treating a disease chosen from rheumatoid arthritis, systemic lupus erythematosus, scleroderma, asthma, allergic rhinitis, allergic eczema, B-cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile ileptic arthritis, intestinal disease graft versus host, psoriatic arthritis, ankylosing spondylitis and uveitis, characterized in that it comprises administering to a patient a therapeutically effective amount of a compound, as defined in claim 1, or a pharmaceutically acceptable salt thereof.
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    同族专利:
    公开号 | 公开日
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB9608435D0|1996-04-24|1996-06-26|Celltech Therapeutics Ltd|Chemical compounds|
    DE60211348T2|2001-08-13|2007-02-08|Janssen Pharmaceutica N.V.|2,4,5-TRISUBSTITUTED THIAZOLYL DERIVATIVES AND THEIR ANTIINFLAMMATORIC EFFECT|
    JP2006515828A|2001-09-27|2006-06-08|スミスクライン・ビーチャム・コーポレイション|Chemical compound|
    FR2881426B1|2005-02-03|2007-03-30|Aventis Pharma Sa|SUBSTITUTED PYROLLES AND IMIDAZOLES, COMPOSITIONS CONTAINING THE SAME, PROCESS FOR FRABRICATION AND USE|
    JP2009536617A|2006-04-11|2009-10-15|バーテックスファーマシューティカルズインコーポレイテッド|Thiazoles, imidazoles, and pyrazoles useful as inhibitors of protein kinases|
    AR063706A1|2006-09-11|2009-02-11|Cgi Pharmaceuticals Inc|CERTAIN AMIDAS REPLACED, THE USE OF THE SAME FOR THE TREATMENT OF DISEASES MEDIATED BY THE INHIBITION OF THE ACTIVITY OF BTK AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM.|
    EP2139487B1|2007-03-28|2015-11-11|Pharmacyclics LLC|Inhibitors of bruton's tyrosine kinase|
    PT2526933E|2006-09-22|2015-06-23|Pharmacyclics Inc|Inhibitors of bruton's tyrosine kinase|
    BRPI0914657A2|2008-06-24|2019-09-24|F Hoffmann La Roche|substituted pyridin-2-one pyridazin-3-ones|
    AU2009275988B2|2008-07-29|2014-03-27|Universite De Liege|A genetic marker test for Brachyspina and fertility in cattle|
    GB0820819D0|2008-11-13|2008-12-24|Sareum Ltd|Pharmaceutical compounds|
    EP2391619A1|2009-01-30|2011-12-07|Millennium Pharmaceuticals, Inc.|Heteroaryls and their use as pi3k inhibitors|
    US8299077B2|2009-03-02|2012-10-30|Roche Palo Alto Llc|Inhibitors of Bruton's tyrosine kinase|
    KR20120096076A|2009-12-17|2012-08-29|메르크 파텐트 게엠베하|Sphingosine kinase inhibitors|
    LT2578585T|2010-05-31|2016-10-10|Ono Pharmaceutical Co., Ltd.|Purinone derivative as btk kinase inhibitor|
    US8859768B2|2010-08-11|2014-10-14|Millennium Pharmaceuticals, Inc.|Heteroaryls and uses thereof|
    AR082590A1|2010-08-12|2012-12-19|Hoffmann La Roche|INHIBITORS OF THE TIROSINA-QUINASA DE BRUTON|
    JP5859640B2|2011-05-17|2016-02-10|エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ|Breton tyrosine kinase inhibitor|
    JP5823616B2|2011-08-17|2015-11-25|エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ|Breton tyrosine kinase inhibitor|
    US8377946B1|2011-12-30|2013-02-19|Pharmacyclics, Inc.|Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors|
    WO2013113097A1|2012-01-31|2013-08-08|Beta Pharma Canada Inc.|Cyclic molecules as bruton's tyrosine kinase inhibitors|
    CN104662018B|2012-04-20|2017-10-24|阿迪维纳斯治疗有限公司|Substituted Heterobicyclic compounds, composition and its medical applications|
    PE20150756A1|2012-08-10|2015-06-03|Boehringer Ingelheim Int|HETEROAROMATIC COMPOUNDS AS BTK INHIBITORS|
    EP2895473A1|2012-09-13|2015-07-22|F.Hoffmann-La Roche Ag|Inhibitors of bruton's tyrosine kinase|
    GEP201606597B|2012-11-02|2017-01-10|Pfizer|Bruton's tyrosine kinase inhibitors|
    CN103848810A|2012-11-30|2014-06-11|北京赛林泰医药技术有限公司|Bruton's tyrosine kinases inhibitor|
    WO2014152114A1|2013-03-15|2014-09-25|Boehringer Ingelheim International Gmbh|Heteroaromatic compounds as btk inhibitors|
    CN105745202A|2013-09-03|2016-07-06|卡尔那生物科学株式会社|Novel 2,6-diaminopyrimidine derivative|
    WO2015116485A1|2014-01-29|2015-08-06|Boehringer Ingelheim International Gmbh|Pyrazole compounds as btk inhibitors|
    US9975882B2|2015-12-16|2018-05-22|Boehringer Ingelheim International Gmbh|Heteroaromatic compounds as BTK inhibitors|PE20150756A1|2012-08-10|2015-06-03|Boehringer Ingelheim Int|HETEROAROMATIC COMPOUNDS AS BTK INHIBITORS|
    GEP201606597B|2012-11-02|2017-01-10|Pfizer|Bruton's tyrosine kinase inhibitors|
    CN103848810A|2012-11-30|2014-06-11|北京赛林泰医药技术有限公司|Bruton's tyrosine kinases inhibitor|
    US8895750B2|2013-03-14|2014-11-25|Boehringer Ingelheim International Gmbh|Heteroaromatic compounds as BTK inhibitors|
    CN112608298A|2013-03-15|2021-04-06|詹森药业有限公司|Process and intermediates for the preparation of a medicament|
    WO2014152114A1|2013-03-15|2014-09-25|Boehringer Ingelheim International Gmbh|Heteroaromatic compounds as btk inhibitors|
    JP6615752B2|2013-09-30|2019-12-04|グアンジョウ・イノケア・ファーマ・テク・カンパニー・リミテッド|Substituted nicotinimide inhibitors of BTK and their preparation and use in the treatment of cancer, inflammation and autoimmune diseases|
    US9512084B2|2013-11-29|2016-12-06|Novartis Ag|Amino pyrimidine derivatives|
    WO2015116485A1|2014-01-29|2015-08-06|Boehringer Ingelheim International Gmbh|Pyrazole compounds as btk inhibitors|
    WO2015185998A2|2014-04-11|2015-12-10|Acerta Pharma B.V.|Methods of blocking the cxcr-4/sdf-1 signaling pathway with inhibitors of bone marrow x kinase|
    CN105085474B|2014-05-07|2018-05-18|北京赛林泰医药技术有限公司|Shandong tyrosine kinase inhibitor|
    CN105884747B|2014-08-28|2021-01-05|首药控股有限公司|Preparation method for preparing Bruton's Tyrosine Kinasekinase inhibitor|
    EP3782994A1|2015-12-16|2021-02-24|Loxo Oncology, Inc.|Compounds useful as kinase inhibitors|
    US9975882B2|2015-12-16|2018-05-22|Boehringer Ingelheim International Gmbh|Heteroaromatic compounds as BTK inhibitors|
    CN105646318A|2015-12-30|2016-06-08|武汉药明康德新药开发有限公司|Synthesis method of 2-tertbutyloxycarbonyl-5-azaspiro[3.3]heptane-6-carboxylic acid|
    US10570118B2|2016-01-13|2020-02-25|Boehringer Ingelheim International Gmbh|Isoquinolones as BTK inhibitors|
    CN107226805A|2016-03-24|2017-10-03|北京天诚医药科技有限公司|Aromatic amides analog derivative, its preparation method and its in application pharmaceutically|
    WO2018033841A1|2016-08-15|2018-02-22|Novartis Ag|Regimens and methods of treating multiple sclerosis using ofatumumab|
    CN107759602B|2016-08-17|2020-04-21|中国科学院上海药物研究所|Compound containing conjugated allene structure, pharmaceutical composition and application thereof|
    MX2019005706A|2016-11-18|2019-07-08|Biocad Joint Stock Co|Inhibitors of bruton's tyrosine kinase.|
    WO2020113094A1|2018-11-30|2020-06-04|Nuvation Bio Inc.|Pyrrole and pyrazole compounds and methods of use thereof|
    KR102200032B1|2019-03-13|2021-01-08|전남대학교산학협력단|Novel compound and composition for the prevention or treatment of respiratory diseases comprising the same|
    EP3942045A1|2019-03-21|2022-01-26|Onxeo|A dbait molecule in combination with kinase inhibitor for the treatment of cancer|
    WO2021089791A1|2019-11-08|2021-05-14|INSERM |Methods for the treatment of cancers that have acquired resistance to kinase inhibitors|
    WO2021148581A1|2020-01-22|2021-07-29|Onxeo|Novel dbait molecule and its use|
    法律状态:
    2019-08-20| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-10-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-08-11| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-08-25| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-10-20| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 7A ANUIDADE. |
    2020-12-08| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|
    2021-10-05| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US201261681684P| true| 2012-08-10|2012-08-10|
    PCT/US2013/054096|WO2014025976A1|2012-08-10|2013-08-08|Heteroaromatic compounds as bruton's tyrosine kinaseinhibitors|
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