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Two Click Compounds as Western Hemisphere Inhibitors

机译：二次点击化合物作为西半球抑制剂

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SHP2 inhibitors and their use in the treatment of diseases are described. Also described are pharmaceutical compositions that comprise them. Claim 1: A compound of the formula (1) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized in that: R⁴ is H or a compound of formula (2);A is a monocyclic or multicyclic cyclopropyl, isocyclopropyl, arilo or heteromorphic compound consisting of 5 to 12 members, provided that heteromorphic compound is not a formula compound (3) or (4);R1 is independent in each case, - H, - D, - c8321;-CN - No. 8309; r8310;-SR83099;-S (O) NR R-S (O) R- 8309th;]- 8309th;]-S (o) No. 8309; (r8310);-S (O) R-8309; s (o) 8309; r8310;-8309; s (o) r8310;-C (O) R o -CO RThere, each tar, aluminum, cyclopentadiene, tar or cyclopentadiene can choose to use one or moreoxo -CN -R-Or83099,-No. 8310,-SR83099;-S (O) NR R-S (O) R- 8309th;]- 8309th;]-S (o) No. 8309; (r8310);-S (O) R-8309; s (o) 8309; r8310;-8309; s (o) r8310;Heterosexual, Aries or heterosexual, andA direct link.-S (O) --S (O) -NH--C (3DCH) --CH- o -S (O) -X¹ is N or C; X² is N or CH; B, including the atoms at the junction points, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 monocyclic or polycyclic heteroaryl, wherein each heterocycle or heteroaryl is optionally substituted with one or more -C₁₋ ₆ alkyl, -OH, -NH₂,oxo heteroarilo heterociclilo - (CH) NH- (CH) OH -CF-CHF o -CH F R es -H -OH -NR R-C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₄₋₈ cycloalkenyl, -C₂₋₆ alkynyl, -NH₂,Halo - c833238331-83288cyclo or isocyclohexane, which contains 1-5 heteroatoms selected from n, s, P and O groups; in these heteroatoms, each tar, acylamine, cyclopentadiene, asphalt, cyclopentadiene or isocyclohexane can be replaced by one or more - Oh, halogen, - no832222;oxo -CN -R-Or83099,-8309; 8310;-SR83099;-S (O) NR R-S (O) R- 8309th;]- 8309th;]-S (o) No. 8309; (r8310);-S (O) R-8309; s (o) 8309; r8310;-8309; s (o) r8310;a. Y2es-nr749191;- (CR) --C (O) --C (R) NH-- (CR) O--C (O) N (R) --N (R) C (O) --S (O) N (R) --N (R) S (O) --N (R) C (O) N (R) --N (R) C (S) N (R) --That's it.-OC (o)..-OC (O) N (R) --N (R) C (O) O--C (o) n (r74919) or -,-N (R) C (S) --C (S) N (R) - o -OC (O) O-There, the link is to the left of Y2,As mentioned before, it is connected with the ring and link on the right side of the square unit,As shown in, it is connected with R3;Rᵃ is independently, in each case, -H, -D, -OH, -C₃₋₈ cycloalkyl or -C₁₋₆ alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH₂,At 2 r7491,a. It can be combined with carbon atoms to form a cyclopentadiene composed of 3 to 8 members; R 749595, c83318cyclo-c833238328cyclo-c833228318cyclo, each composed of 1 to 5 heteroatoms selected from n, s, P and O groups; Where every tar, cyclopropyl, acylpropyl or heterocycle can be subjected to one or more - Oh, halogen,oxo -CN -R-Or83099,-8309; 8310;-SR83099;-S (O) NR R-S (O) R- 8309th;]- 8309th;]-S (o) No. 8309; (r8310);-S (O) R-8309; s (o) 8309; r8310;-8309; s (o) r8310;heterocycle, aryl, heteroaryl, - (CH₂) ₙOH, -C₁₋₆ alkyl, -CF₃,-CHF₂ or -CH₂F; R³ is -H, -C₁₋₆ alkyl, a 3 to 12 membered monocyclic or polycyclic heterocycle, -C₃₋₈ cycloalkyl or - (CH₂) ₙ-Rᵇ,wherein each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more -C₁₋₆ alkyl, -OH, -NH₂,-Or 74955,-NHR74959,- (CH₂) ₙOH, heterocyclyl or spiroheterocyclyl; or R³ can be combined with Rᵃ to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -C₁₋₆ alkyl, -OH, -NH₂,oxo heteroarilo heterociclilo - (CH) NH- (CH) OH -CF-CHF₂ or -CH₂F, provided that the heterocycle formed by the combination of R³ and Rᵃ is not an optionally substituted piperazinyl; R⁵ and R⁶ are independently, in each case, -H, -D, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₄₋₈ cycloalkenyl, -C₂₋₆ alkynyl, -C₃₋₈ cycloalkyl, a heterocycle monocyclic or polycyclic with 3 to 12 members, -OR⁷,-SR8311;Halogen, No. 8311; r8322;-NO₂ or -CN; R⁷ and R⁸ are independently, in each case, -H, -D, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₄₋₈ cycloalkenyl, -C₂₋₆ alkynyl, -C₃₋₈ cycloalkyl or a heterocycle monocyclic or polycyclic of 3 to 12 members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more -OH, -SH, -NH₂,-No. 8322o-cn; m is independent, in each case, 1, 2, 3, 4, 5 or 6; n is independent, in each case, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
机译：描述了SHP2抑制剂及其在疾病治疗中的用途。还描述了包含它们的药物组合物。 1，式（1）化合物或其药学上可接受的盐，前药，溶剂化物，水合物，互变异构体或异构体，其特征在于：R 4为H或式（2）化合物; A为单环或多环环丙基，异环丙基，芳基或由5至12个成员组成的多晶型化合物，条件是多晶型化合物不是通式化合物（3）或（4）; R1在每种情况下均独立于-H，-D，-c8321; -CN -第8309号; r8310; -SR83099; -S（O）NR R-S（O）R-830​​9;]-8309th;]-S（o）No. 8309; （r8310）;-S（O）R-830​​9; （o）8309; r8310; -8309;其中，每个焦油，铝，环戊二烯，焦油或环戊二烯均可选择使用一种或多种羰基-CN -R-Or83099，-No。 8310，-SR83099; -S（O）NR R-S（O）R-830​​9;]-8309th;]-S（o）No. 8309; （r8310）;-S（O）R-830​​9; （o）8309; r8310; -8309; s（o）r8310;异性，白羊或异性，以及直接链接。-S（O）-S（O）-NH-C（3DCH）-CH- o -S（O）-X¹是N或C; X 2是N或CH; B，包括在连接点处的原子，是5至12元单环或多环杂环或5至12元单环或多环杂芳基，其中每个杂环或杂芳基任选地被一个或多个-C 1-4烷基，-OH取代，-NH 2，氧杂杂芳基-（CH）NH-（CH）OH -CF-CHF o -CH FR es -H -OH -NR R-C 1-6烷基，-C 2-3烯基，-C 1-6环烯基-C 23炔基，-NH 2，卤代-c833238331-83288环或异环己烷，其含有1-5个选自n，s，P和O基团的杂原子;在这些杂原子中，每一个焦油，酰基胺，环戊二烯，沥青，环戊二烯或异环己烷都可以被一个或多个-OH，卤素，-no832222;氧-CN -R-Or83099，-8309取代; 8310; -SR83099; -S（O）NR R-S（O）R-830​​9th;]-8309th;]-S（o）No.8309; （r8310）;-S（O）R-830​​9; （o）8309; r8310; -8309; s（o）r8310; a。 Y2es-nr749191;-（CR）--C（O）--C（R）NH--（CR）O--C（O）N（R）--N（R）C（O）--S （O）N（R）--N（R）S（O）--N（R）C（O）N（R）--N（R）C（S）N（R）-就是这样。 -OC（o）..- OC（O）N（R）--N（R）C（O）O–C（o）n（r74919）或-，-N（R）C（S）- -C（S）N（R）-o -OC（O）O-在那里，链接位于Y2的左侧，如前所述，它与环相连，并位于方形单元的右侧，如图所示，它与R 3连接;在每种情况下，R 4独立地是-H，-D，-OH，-C 1-6环烷基或-C 1-4烷基，其中每个烷基或环烷基任选地被一个或多个取代。 -NH 2，在2 r7491处，a。它可以与碳原子结合形成由3至8个成员组成的环戊二烯; R 749595，c83318cyclo-c833238328cyclo-c833228318cyclo，每个由1至5个选自n，s，P和O组的杂原子组成;其中每个焦油，环丙基，酰基丙基或杂环均可以经受一个或多个-卤素，氧代-CN -R-Or83099，-8309; 8310; -SR83099; -S（O）NR R-S（O）R-830​​9th;]-8309th;]-S（o）No.8309; （r8310）;-S（O）R-830​​9; （o）8309; r8310; -8309; s（o）r8310;杂环，芳基，杂芳基，-（CH 2）OH，-C 1烷基，-CF 3，-CHF 2或-CH 2 F; R 3是-H，-C 6烷基，3至12元单环或多环杂环，-C 3环烷基或-（CH 2）1-4 -R 4，其中每个烷基，杂环或环烷基任选地被一个或多个-取代。 C 6烷基，-OH，-NH 2，-或74955，-NHR74959，-（CH 2）＝ OH，杂环基或螺杂环基; R 3或R 3可以与R 5结合形成3至12元单环或多环杂环或5至12元螺杂环，其中每个杂环或螺杂环任选地被一个或多个-C 1烷基，-OH，-NH 2取代，氧杂杂芳基杂环基-（CH）NH-（CH）OH-CF-CHF 2或-CH 2 F，条件是由R 3和R 4结合形成的杂环不是可取代的哌嗪基; R 5和R 6在每种情况下分别独立地为-H，-D，-C 6烷基，-C 20链烯基，-C 5环烯基，-C 20炔基，-C 4环烷基，杂环单环或具有3至12个成员的多环，-OR⁷，-SR8311;卤素，编号8311; r8322; -NO 2或-CN; R 5和R 6分别独立地是-H，-D，-C 1烷基，-C 20链烯基，-C 4环烯基，-C 20炔基，-C 4环烷基或杂环单环或3至12个成员的多环，其中每个烷基，烯基，环烯基，炔基，环烷基或杂环任选地被一个或多个-OH，-SH，-NH 2，-No取代。 8322o-cn; m分别独立地是1、2、3、4、5或6; n分别独立地是0、1、2、3、4、5、6、7、8、9或10;

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