TWI827869B - Substituted pyrrolo [2, 3-b] pyridine and pyrazolo [3,4-b] pyridine derivatives as protein kinase inhibitors - Google Patents

Abstract

The present invention provides a type of BTK inhibitor, its pharmaceutical composition and its use method.

Description

Substituted pyrrolo[2,3-b]pyridines and pyrazolos as protein kinase inhibitors [3,4-b]pyridine derivatives

The present invention relates to a class of compounds that can inhibit the activity of Bruton's tyrosine kinase (BTK) or pharmaceutically acceptable salts thereof, and as pharmaceuticals for the treatment of hyperproliferative diseases such as cancer and inflammation, or immune and autoimmune diseases.

Hyperproliferative diseases such as cancer and inflammation attract the academic community to provide effective treatments. Efforts have been made in this regard to identify and target specific mechanisms that play a role in proliferative diseases.

Bruton's tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases. It is expressed in B cells and myeloid cells and plays a key regulatory role in the B cell receptor (BCR) pathway. The B cell receptor pathway is involved in early B cell development, mature B cell activation, signaling and survival.

The known cause of X-linked agammaglobulinemia (XLA) is a functional mutation of human BTK. It is a primary human disease in which the functional mutation fails to produce mature B cells, resulting in a significant reduction or lack of various types of immunoglobulins in the serum. Immunodeficiency diseases. In addition, modulating BTK can induce B cells to produce pro-inflammatory cytokines and chemokines through the B cell receptor pathway, indicating that BTK has broad potential in the treatment of autoimmune diseases. BTK in autoimmune and inflammatory diseases The role in disease treatment has also been confirmed in a BTK-deficient mouse model. Therefore, inhibiting BTK activity may be useful in the treatment of autoimmune and/or inflammatory diseases such as rheumatoid arthritis, polyvasculitis, myasthenia gravis, and asthma.

In addition, BTK has been reported to play an important role in apoptosis. In some malignant tumors, BTK is overexpressed in B cells, which is associated with tumor cell proliferation and survival. Inhibiting BTK can prevent B cell activation and inhibit malignant B cell growth by affecting B cell signal transduction pathways.

Therefore, inhibition of BTK activity could be used to treat cancers such as B-cell lymphomas, leukemias, and other hematological malignancies. Numerous clinical trials have shown that BTK inhibitors are effective against cancer. Ibrutinib (PCI-32765) is the first BTK inhibitor approved by the U.S. Food and Drug Administration for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and Waldenstrom's macroglobulinemia (WM). BTK inhibitors may also be used to treat other diseases, such as immune disorders and inflammation.

Therefore, compounds with BTK inhibitory activity, including mutant BTK inhibitory activity, are of great significance for the prevention and treatment of the above diseases. Although BTK inhibitors have been reported in the literature, such as WO 2008039218 and WO 2008121742, many inhibitors have short half-lives or are toxic. Therefore, there is still an urgent need for new BTK inhibitors that have advantages in at least one aspect of efficacy, stability, selectivity, safety and pharmacodynamic characteristics in the treatment of hyperproliferative diseases. Based on this, the present invention relates to a new class of BTK inhibitors.

The present invention relates to a new class of compounds, their pharmaceutically acceptable salts and their pharmaceutical compositions, as well as their use as medicines.

In one aspect, the invention provides compounds of formula (I):

Or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are respectively ^{Unsubstituted} _or ^substituted by ^{at least} _one substituent _{independently} ^{selected from R} -(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t - and -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -; X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X' and N; Y is selected from CR ⁴ and N; R ¹ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O) OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , - NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S(O)R ^A1 R ^B1 , -S( O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P( O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is respectively ^Substituted or ^{substituted by} _at ^{least one} substituent independently selected ^{from R} C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from R ^X2 ; R ³ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , -C(O)NR ^A2 R ^B2 and C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from R ^X3 ; R ⁴ is selected from hydrogen, halogen, CN , NO ₂ , -NR ^A4 R ^B4 , -OR ^A4 and C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from ^RX4 ; R ⁵ is selected from hydrogen, halogen , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, hetero Cyclic group - C _1-4 alkyl, aryl, aryl - C _1-4 alkyl, heteroaryl, heteroaryl - C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , - OR ^A5 , -C(O)R ^A5 , -C(=NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 ,- C(O)NR ^A5 R ^B5 , -NR ^A5 C(O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S(O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 ) NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O) (OR ^A5 )(OR ^B5 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is individually unsubstituted or independently selected from R ^X5 Substituted with substituents; each R ^A0 and R ^B0 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 Cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _{1- 4} alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X0 ; or Each " ^RA0 and R ^B0 " together with the single or multiple atoms to which they are attached constitute a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus. _, the ring may be optionally substituted _by ¹ _, ² or 3 ^R Alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _{1- 4Alkyl} , Heteroaryl and Heteroaryl-C _1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or ^be substituted by at ^least one substituent independently selected from ^R 4-12 membered heterocyclic ring with heteroatoms of sulfur, nitrogen and phosphorus, the ring may be optionally substituted by 1, 2 or 3 R ^X1 groups; each R ^A2 and R ^B2 are independently selected from hydrogen, C _{1- 10} alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4} alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl ^are unsubstituted ^or substituted with at least one substituent independently selected from ^R Constituting a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted by 1, 2 or 3 R ^X2 groups; Each R ^A3 and R ^B3 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where Each alkyl, alkenyl ^, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^R and R ^B3 ″ together with single or multiple atoms connected to them form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be any Optionally _substituted by ₁ ^{, 2} _or ³ _{R -10} cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, hetero Aryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or independently Substituted with ^{a substituent} selected from ^R A 4-12 membered heterocyclic ring of heteroatoms, which ring may be optionally substituted by 1, 2 or 3 R ^X4 groups; each R ^A5 and R ^B5 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C 3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- _{C 1-4} alkyl , aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl are unsubstituted ^or substituted with ^at least one substituent independently selected from ^R or 2 additional 4-12 membered heterocycles with heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which rings may be optionally substituted with 1, 2 or 3 R ^X5 groups; each R ^C0 and R ^D0 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 Alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl radical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted by at least one substituent independently selected from R ^X0 ; or R ^C0 and R ^D0 together with The single or multiple carbon atoms they are connected to constitute a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally surrounded by 1, 2 or 3 ^R Group substitution; each R ^E0 , R ^E1 and R ^E5 are independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C (O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ; each R ^X , R ^X' , R ^X0 , R ^X1 , _R ^X2 , _R ^X3 _{, R} ^X4 _and ^R Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, halogen, CN, -NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O) NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) (=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -( CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^e1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are unsubstituted or substituted with at least one substituent independently selected from R ^Y ; each R ^a1 and R ^b1 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C 3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl ,} aryl, aromatic Base - C _1-4 alkyl, heteroaryl and heteroaryl - C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y ; or R ^a1 and R ^b1 together with the single or multiple atoms to which they are attached contain 0, 1 or 2 additional substituents independently selected from oxygen , a 4-12 membered heterocyclic ring with heteroatoms of sulfur, nitrogen and phosphorus, the ring may be optionally substituted by 1, 2 or 3 R ^Y groups; each R ^c1 and R ^d1 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl} , heterocyclyl, heterocycle base-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with at least one substituent independently selected from R ^Y ; or R ^c1 and R ^d1 together with the single or multiple carbon atoms to which they are attached Constituting a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring may be optionally substituted by 1, 2 or 3 R ^Y groups; each R ^e1 is independently Selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S( O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ; each R ^Y is selected independently From C _1-10 alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl} , heterocyclyl, hetero Cyclic group-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P (O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P( O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)R ^a2 , -C(O) (CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, -C (O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ) , -C(=NR ^e2 )R ^a2 , -C(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C(= NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is unsubstituted or at least one independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di( C _1-10 alkyl) amino substituent substitution; each R ^a2 and R ^b2 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkyl Thio group, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl- C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio , cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _{1 -10} alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents substitution; or R ^a2 Together with R ^b2 and the single or multiple atoms connected to them, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be optional. 1 or 2 ground covers are independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy group, C _3-10 cycloalkoxy group, C _1-10 alkylthio group, C _3-10 cycloalkylthio group, amino group, C _1-10 alkylamino group, C _3-10 cycloalkylamino group and di(C _{1- 10} alkyl) amino substituent substitution; Each R ^c2 and R ^d2 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 ring Alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio Base, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, Cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkene Base, C _2-10 alkynyl group, C _3-10 cycloalkyl group, hydroxyl group, C _1-10 alkoxy group, C _3-10 cycloalkoxy group, C _1-10 alkylthio group, C _3-10 cycloalkyl group Substituents of thio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino; or R ^c2 and R ^d2 together with single or multiple single or multiple carbon atoms forming a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring may be optionally replaced by 1 or 2 independently selected from halogen, CN, C _{1- 10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkyl Substituents for thio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino; each R ^e2 is independently selected From hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 Cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _{3- 10} cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl , -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ; Each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4; each u is independently selected from 0, 1, 2, 3, and 4.

[11] In one embodiment of formula (1), the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ , and the compound is represented by formula (II):

The definitions of Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are the same as those in formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method for modulating BTK, the method comprising administering to a system or individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, thereby modulating BTK.

On the other hand, the present invention also provides a method for treating, improving or preventing conditions that respond to inhibition of BTK, comprising administering to a system or individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. The pharmaceutical composition, or optionally in combination with another therapeutic agent, treats the above conditions.

Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disorder mediated by BTK. In certain embodiments, the compounds may be used alone or in combination with another therapeutic agent to treat a BTK-mediated disorder.

Alternatively, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of BTK-mediated disorders.

Specifically, the disorder includes, but is not limited to, autoimmune diseases, xenoimmune diseases, allergic diseases, inflammatory diseases or cell proliferation abnormalities.

Furthermore, the present invention provides a method of treating a BTK-mediated disorder comprising administering to a system or individual in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, or optionally combined with Another therapeutic drug is used in combination to treat the above conditions.

Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt in the preparation of a medicament for treating diseases mediated by BTK. In certain embodiments, the compounds may be used alone or in combination with chemotherapeutic agents to treat the above-described cell proliferation abnormalities.

In particular, the disorder includes, but is not limited to, autoimmune diseases, xenoimmune diseases, allergic diseases, inflammatory diseases or cell proliferation abnormalities.

In certain embodiments, the condition is abnormal cell proliferation. In a certain embodiment, the cell proliferation abnormality is a B cell proliferation abnormality, including but not limited to, B cell malignant tumors, B cell chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic cell lymphoma, multiple sclerosis, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin lymphoma, activated B-cell-like diffuse large B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma B-cell lymphoma, follicular lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, lymphomatoid granulomatosis, and plasmacytoma.

In certain embodiments, the disorder is an autoimmune disease, including, but not limited to, rheumatoid arthritis, psoriatic arthritis, psoriasis, osteoarthritis, juvenile arthritis, inflammatory disease Enteropathy, Crohn's disease, ulcerative colitis, myasthenia gravis, Hashimoto's thyroiditis, multiple sclerosis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, Aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis disease, autonomic dysfunction, neuromyotonia, interstitial cystitis, lupus erythematosus, systemic lupus erythematosus and lupus nephritis.

In certain embodiments, the disorder is a xenoimmune disease, including, but not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, Allergic rhinitis and atopic dermatitis.

In certain embodiments, the condition is an inflammatory disease, including, but not limited to, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, synovitis, cervicitis, cholangitis, cholecystitis, colitis, Conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis , gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis , peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis , vaginitis, vasculitis and vulvitis.

In the above methods of using the compounds of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a system containing cells or tissues, or to an individual including a mammalian subject, such as a human or animal subject. .

Terminology

Unless otherwise defined, all technical and scientific terms used in this patent have the same meaning as commonly understood by professionals in the field. Unless otherwise stated, all patents, patent applications, publicly disclosed materials, etc. referenced in this patent are incorporated by reference in their entirety. If there are multiple definitions for the same term in this patent, the definition in this section shall prevail.

It should be understood that the foregoing general description and the following detailed description are for explanatory purposes only and are not restrictive of any claim. In this patent application, the use of the singular includes the plural unless otherwise stated. It should be noted that in the description and attached claims, singular forms such as "a", "an", and "this" include plural references unless otherwise stated in the context. Also note that "or" means "and/or" unless stated otherwise. In addition, the terms "includes," "includes," and similar terms are not limiting.

Unless otherwise stated, the conventional techniques of mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacology used in this patent are state of the art. Unless otherwise defined, the nomenclature, experimental methods and techniques involved in analytical chemistry, organic synthetic chemistry, pharmaceutical and pharmaceutical chemistry in this patent are all known. Standard techniques are used for chemical synthesis, chemical analysis, drug preparation, formulation and administration, and treatment of patients. Reaction and purification techniques can be carried out by referring to the manufacturer's instructions, or by referring to known commonly used techniques, or by referring to the methods described in this patent. The above-mentioned techniques and operations can be implemented using known conventional methods and methods cited in the literature cited in this specification. In the specification, groups and substituents can be selected by those skilled in the art to form stable structures and compounds.

When a chemical formula is used to refer to a substituent, writing the substituent in the formula from left to right is the same as writing it from right to left. For example, _CH2O is the same as _OCH2 .

"Substitution" means that a hydrogen atom is replaced by a substituent. It is important to note that substituents on a specific atom are constrained by their valence.

As used herein, the term "C _ij " or "ij element" means that the moiety has ij carbon atoms or ij atoms. For example, "C _1-6 alkyl" means that the alkyl group has 1-6 carbon atoms. Likewise, C _3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.

When any variable (such as R) appears more than once in the structure of a compound, it is defined independently in each case. Thus, for example, if a group is substituted by 0-2 R, then the group may optionally be substituted by up to two R, with R being independently selected in each case. Additionally, combinations of substituents and/or variations thereof are allowed only if such combinations will result in stable compounds.

"One or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

Unless otherwise stated, the term "hetero" refers to heteroatoms or groups of heteroatoms (i.e., groups containing heteroatoms), that is, atoms other than carbon and hydrogen atoms or groups containing these atoms. Preferably, the heteroatoms are independently selected from O, N, S, P, etc. In embodiments involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be partially or entirely different.

"Alkyl", whether used alone or in combination with other terms, refers to a branched or straight-chain saturated aliphatic hydrocarbon group with a specific number of carbon atoms. Unless otherwise stated, "alkyl" refers to C ₁ - ₁₀ alkyl. For example, "C ₁ - ₆ " in "C ₁ - ₆ alkyl" refers to a linear or branched group with 1, 2, 3, 4, 5 or 6 carbon atoms. For example, "C _{1 -8} alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl .

"Cycloalkyl", whether used alone or in combination with other terms, refers to a saturated monocyclic or polycyclic (eg, bicyclic or tricyclic) hydrocarbon ring system, typically having 3 to 16 ring atoms. The ring atoms of a cycloalkyl group are all carbon, and a cycloalkyl group contains zero heteroatoms and zero double bonds. In polycyclic cycloalkyl groups, two or more rings may be fused or bridged or spiro together. Examples of monocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bridged cycloalkyl is a polycyclic ring system containing 3 to 10 carbon atoms, which contains one or two alkylene bridges, each consisting of 1, 2 or 3 carbon atoms, connecting the ring system Two non-adjacent carbon atoms. Cycloalkyl groups can be fused to aryl or heteroaryl groups. In some embodiments, the cycloalkyl group is benzo-fused. Representative examples of bridged cycloalkane systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, Bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). Monocyclic and bridged hydrocarbon rings can be attached to the parent molecular moiety through any substitutable atom in the ring system.

"Alkenyl", whether used alone or in combination with other terms, refers to a non-aromatic straight-chain, branched or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, 1 carbon-carbon double bond is present and up to 4 non-aromatic carbon-carbon double bonds may be present. Therefore, "C ₂ - ₆ alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The linear, branched, or cyclic portion of an alkenyl group may contain double bonds, and if substituted alkenyl is indicated, it may be substituted.

"Alkynyl", whether used alone or in combination with other terms, refers to a straight-chain, branched or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to 3 carbon-carbon triple bonds may be present. Therefore, "C ₂ - ₆ alkynyl" refers to an alkynyl group containing 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The linear, branched or cyclic portion of an alkynyl group may contain triple bonds, and if a substituted alkynyl group is indicated, it may be substituted.

"Halogen" refers to fluorine, chlorine, bromine, and iodine.

"Alkoxy", used alone or in combination with other terms, means an alkyl group as defined above attached to an oxygen atom by a single bond. The alkoxy group is attached to the molecule through an oxygen atom. Alkoxy can be represented as -O-alkyl. "C _1-10 alkoxy" refers to an alkoxy group containing 1-10 carbon atoms, which can be a straight chain or branched structure. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.

"Cycloalkoxy", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to an oxygen atom by a single bond. The cycloalkoxy group is attached to the molecule through an oxygen atom. Cycloalkoxy can be represented as -O-cycloalkyl. "C _3-10 cycloalkoxy" refers to a cycloalkoxy group containing 3 to 10 carbon atoms. Cycloalkoxy groups can be fused to aryl or heteroaryl groups. In some embodiments, cycloalkoxy groups are benzo-fused. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.

"Alkylthio", used alone or in combination with other terms, refers to an alkyl group as defined above attached to a sulfur atom by a single bond. The alkylthio group is attached to the molecule through a sulfur atom. Alkylthio groups may be represented as -S-alkyl. "C _1-10 alkylthio group" refers to an alkylthio group containing 1-10 carbon atoms, which can be a straight chain or branched structure. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

"Cycloalkylthio", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a sulfur atom by a single bond. The cycloalkylthio group is attached to the molecule through a sulfur atom. Cycloalkylthio may be represented as -S-cycloalkyl. "C _3-10 cycloalkylthio" refers to a cycloalkylthio group containing 3 to 10 carbon atoms. A cycloalkylthio group may be fused to an aryl or heteroaryl group. In some embodiments, the cycloalkylthio group is benzo-fused. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

"Alkylamino", used alone or in combination with other terms, refers to an alkyl group as defined above attached to a nitrogen atom by a single bond. The alkylamino group is linked to another molecule through a nitrogen atom. Alkylamino groups can be represented as -NH (alkyl). "C _1-10 alkylamino" refers to an alkylamino group containing 1-10 carbon atoms, which can be a straight chain or branched structure. Alkylamino groups include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group and hexamino group.

"Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a nitrogen atom by a single bond. The cycloalkylamino group is linked to another molecule through a nitrogen atom. Cyclalkylamino can be represented as -NH (cycloalkyl). "C _3-10 cycloalkylamino" refers to a cycloalkylamino group containing 3-10 carbon atoms. A cycloalkylamino group can be fused to an aryl or heteroaryl group. In some embodiments, the cycloalkylamino is benzo-fused. Cyclalkylamino groups include, but are not limited to, cyclopropylamino group, cyclobutylamino group, cyclohexylamino group, and the like.

"Di(alkyl)amino", used alone or in combination with other terms, refers to two alkyl groups as defined above connected to a nitrogen atom by a single bond. The di(alkyl)amino group is attached to the molecule through a nitrogen atom. Di(alkyl)amino group may be represented as -N(alkyl) ₂ . "Di(C _1-10 alkyl)amino" refers to a di(C _1-10 alkyl)amino group whose two alkyl moieties each contain 1-10 carbon atoms, and can be a straight chain or branched structure.

"Aryl", used alone or in combination with other terms, means a group having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C _6-14 aryl" group) Monovalent, monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring systems, especially rings with 6 carbon atoms ("C ₆ aryl" groups), such as phenyl; or rings with 10 carbon atoms ("C ₁₀ "aryl" group), such as naphthyl; or a ring with 14 carbon atoms ("C ₁₄ aryl" group), such as anthracenyl. Aryl groups can be fused to cycloalkyl or heterocyclyl groups.

A divalent group formed from a substituted benzene derivative and having free valence electrons on the ring atom is named a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends with "-", which is obtained by removing a hydrogen atom from a carbon atom containing free valence electrons. Its name is the monovalent group. Add "-idene" to the name. For example, a naphthyl group with two attachment sites is called a naphthylene group.

"Heteroaryl", used alone or in combination with other terms, means a group having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms ("5 to 14 membered heteroaryl" group) a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system, in particular 5 or 6 or 9 or 10 atoms, and containing at least one heteroatom which may be the same or different, said heteroatom being selected from N, O and S, the remaining atoms in the ring are carbon atoms. Heteroaryl groups can be fused to cycloalkyl or heterocyclyl groups. In some embodiments, "heteroaryl" refers to

A 5- to 8-membered aromatic monocyclic ring, the ring contains 1 to 4, in some embodiments, 1 to 3 heteroatoms selected from N, O and S, and the rest are carbon atoms; Or an 8- to -12-membered bicyclic aromatic ring containing heteroatoms selected from N, O, and S in number from 1 to 6, in certain embodiments from 1 to 4, or in certain embodiments In this case, there are 1 to 3 heteroatoms, and the rest are carbon atoms; or 11 to 14 membered tricyclic aromatic rings, the rings containing rings selected from N, O and S, numbering from 1 to 8, in certain embodiments from 1 to 6, or in certain embodiments There are 1 to 4, or in some embodiments 1 to 3, heteroatoms in number, and the remainder are carbon atoms.

When the total number of S and O in a heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O in the heteroaryl group is no greater than 1.

Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl , 6-pyrimidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, Pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, furyl.

Further, heteroaryl groups include, but are not limited to, indolyl, benzothienyl, benzofuryl, benzimidazolyl, benzotriazolyl, quinoxalyl, quinolyl and isoquinolyl. "Heteroaryl" includes the N-oxide derivative of any nitrogen-containing heteroaryl.

The name of the monovalent heteroaryl group ends with "-", and the derived divalent group is obtained by removing a hydrogen atom from the carbon atom containing free valence electrons. The divalent group The naming is based on adding "-idene" to the name of the monovalent group. For example, a pyridyl group with two connection sites is called a pyridyl group.

"Heterocycle" (and its derivatives such as "heterocycle" or "heterocyclyl") generally refers to a saturated or non-containing, monocyclic or polycyclic (such as bicyclic) cyclic aliphatic hydrocarbon system, usually with 3 to 12 ring atoms, containing at least 1 (e.g. 2, 3 or 4) ring atoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus atoms (preferably oxygen, sulfur, nitrogen), and the remaining atoms in the ring are carbon atoms. In polycyclic systems two or more rings can be linked by fusion, bridging or spiro rings, and heterocycles can be fused with aryl or heteroaryl groups. In some embodiments, the heterocycle is benzo-fused. Heterocycles also include ring systems substituted with one or more oxo or imino moieties. In some embodiments, the C, N, S and P atoms in the heterocycle are optionally substituted with oxo. In some embodiments, the C, S and P atoms in the heterocycle are optionally substituted with imino groups, and the imino groups may be unsubstituted or substituted. Carbon atoms or heteroatoms on the heterocyclic ring can be the connection sites, provided a stable structure is formed. When there is a substituent on the heterocycle, the substituent can be connected to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure is formed.

Suitable heterocycles include, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, 4-imidazolidinyl, 5 -Imidazolidinyl, 1-pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 1-pyrazolidinyl, 2-pyrazolidinyl base, 3-pyridinyl, 4-pyridinyl, 1-pyridinyl, 2-pyridinyl, 3-pyridinyl, 1-hexahydropyridazinyl, 3-hexahydropyridazinyl and 4- Hexahydropyridazinyl. Examples of heterocycles having one or more oxo moieties include, but are not limited to, piridinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl and 1,1- Dioxo-thiomorpholinyl. Bicyclic heterocycles include but are not limited to:

"Aryl-alkyl" as used herein refers to an alkyl group as defined above substituted by an aryl group as defined above. Exemplary aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like. In some implementations, aralkyl groups contain 7-20 or 7-11 carbon atoms. When "aryl C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms in the alkyl part rather than the aryl part.

"Heterocyclyl-alkyl" as used herein means a heterocyclyl group as defined above substituted for an alkyl group as defined above. When "heterocyclyl C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms in the alkyl part rather than the heterocyclyl part.

"Cycloalkyl-alkyl" as used herein refers to an alkyl group as defined above substituted by a cycloalkyl group as defined above. When "C _3-10 cycloalkyl-C _1-4 alkyl" is used, "C _3-10 " refers to the number of carbon atoms in the cycloalkyl part rather than the alkyl part. Where "C _1-4 " refers to the number of carbon atoms in the alkyl part rather than the cycloalkyl part.

"Heteroaryl-alkyl" as used herein refers to an alkyl group as defined above substituted by a heteroaryl group as defined above. When "heteroaryl-C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms in the alkyl portion rather than the heteroaryl portion.

To avoid ambiguity, for example: when referring to alkyl, cycloalkyl, heterocyclylalkyl, aryl, and/or heteroaryl substitution thereof, it is meant that each of these groups is individually substituted, or Refers to the mixed substitution of these groups. That is: if R is aryl-C _1-4 alkyl, and may be unsubstituted or substituted with at least one substituent, such as 1, 2, 3 or 4 substituents independently selected from ^R It should be understood that the aryl moiety may be unsubstituted or substituted with at least one, such as 1, 2, 3 or 4 substituents independently selected from ^R For example, 1, 2, 3 or 4 substituents independently selected from R ^X are substituted.

"Pharmaceutically acceptable salts" refers to salts made with pharmaceutically acceptable non-toxic salts or acids, including inorganic or organic salts and inorganic or organic acids. The salt of the inorganic salt may be selected from, for example: aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc salts. Further, pharmaceutically acceptable salts of inorganic salts may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. One or more crystalline forms, or polymorphs, may exist in solid salts, and solvates, such as hydrates, may also exist. Pharmaceutically acceptable salts of organic non-toxic amines may be selected from, for example: primary, secondary and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as arginine, beet Caffeine, caffeine, choline, N,N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -ethylmorpholine, N -ethylpyridine, glucosamine, glucosamine, histidine, hypamine, isopropylamine, lysine, meglucosamine, morpholine, pyridine, glucosamine, polyamine resin, pluca Because, purine, cocoaline, triethylamine, trimethylamine, tripropylamine, tromethamine.

When the compound referred to in this patent is a salt, it is necessary to prepare its salt with at least one pharmaceutically acceptable non-toxic acid, and these acids are selected from inorganic acids and organic acids. For example, selected from acetic acid, benzenesulfonic acid, Benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane Sulfonic acid, mucic acid, nitric acid, parapic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid. In some embodiments, these acids may be selected, such as: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, tartaric acid.

"Administering" or "administering" a compound or a pharmaceutically acceptable salt thereof means providing a compound of the invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.

"Effective amount" refers to the amount of a compound or a pharmaceutically acceptable salt thereof that causes a biological or medical response in tissues, systems, animals, or humans that is observable by researchers, veterinarians, clinicians, or other clinical personnel.

"Composition" includes: products containing specific ingredients in specific amounts, and any product that is a direct or indirect combination of these specific ingredients in specific amounts. Pharmaceutical compositions, including: products containing active ingredients and inert ingredients as carriers, and products made from any two or more ingredients, directly or indirectly, by combination, compounding or aggregation, or by one or more A product produced by the decomposition of ingredients, or by other types of reactions or interactions of one or more ingredients.

"Pharmaceutically acceptable" means compatible with other ingredients in the preparation and not unacceptably toxic to the user.

"Individual" refers to an individual suffering from a disease, disorder or the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, mianyangs, mountain animals Sheep and pigs; domestic animals such as rabbits, dogs and cats; experimental animals including rodents such as rats, mice and guinea pigs. Non-mammals include, but are not limited to, birds, fish, etc. In one embodiment of the invention, the mammal is a human.

"Treatment" includes alleviating, alleviating or ameliorating a disease or symptoms, preventing other symptoms, ameliorating or preventing underlying metabolic factors of symptoms, inhibiting a disease or symptoms, e.g., preventing the progression of a disease or symptoms, alleviating a disease or symptoms, promoting remission of a disease or symptoms, or the cessation of symptoms of a disease or condition, and extends to include prevention. "Treatment" also includes achieving therapeutic benefit and/or preventive benefit. Therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, therapeutic benefit is achieved by eradication or amelioration of one or more physiological signs associated with the underlying disease, whereby improvement in the patient's disease is observed although the patient may still have the underlying disease. Prophylactic benefit refers to use of a composition by a patient to prevent the risk of a disease or when the patient is experiencing one or more physiological symptoms of the disease, although the disease has not yet been diagnosed.

"Protecting group" (Pg) refers to a type of substituent used to react with other functional groups on a compound to block or protect a specific functional group. For example, an "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality on a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl protecting group (Fmoc). Likewise, "hydroxyl protecting group" refers to a type of hydroxyl substituent that can effectively block or protect the hydroxyl function. Suitable protecting groups include, but are not limited to, acetyl and silyl. "Carboxyl protecting group" refers to a type of carboxyl substituent that can effectively block or protect the carboxyl group. Commonly used carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl) Ethyl, 2-(p-nitrobenzene sulfenyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description of protective groups and instructions for their use, see reference: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 .

"NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl base, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, Isopropoxycarbonyl, phthalyl, succinyl, alaninyl, leucinyl, 1-adamantoxycarbonyl, 8-quinolyloxycarbonyl, benzyl, benzyl, tris Benzyl, 2-nitrobenzenethio, methanesulfonyl, p-toluenesulfonyl, N,N -dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2- Hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2- Ethoxycarbonyl cyclopentylene, 2-acetyl cyclohexylene, 3,3-dimethyl-5-oxycyclohexylene, diphenylphosphoryl, dibenzylphosphonyl, 5-methyl yl-2-oxy- 2H -1,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

The "C(O)OH" protecting group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, Naphthyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzylmethyl , p-Nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methylsulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl base, 2-(trimethylsilyl)ethyl, acetyloxymethyl, propionyloxymethyl, pivalyloxymethyl, phthalylimidemethyl, succinyl Imidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, Benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3- Butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenyl silyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

The "OH or SH" protecting group includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2, 2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy- 1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formic acid, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxy Acetyl, phenoxyacetyl, pivalyl, benzyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1 ,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxy Benzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl , 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, Methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyl diphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

Geometric isomers may exist in the compounds of the invention. The compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where "E" represents that according to the Cahn-Ingold-Prelog priority rule, the preferred substituent is in the carbon-carbon double bond or carbon -The opposite side of the nitrogen double bond, and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or the carbon-nitrogen double bond. The compounds of the present invention may also exist as mixtures of "E" and "Z" isomers. Substituents surrounding a cycloalkyl or heterocyclyl group may be in the cis or trans configuration. Furthermore, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. The two substituents surrounding a single ring in the adamantane ring system are designated as the Z or E relative configuration. See, for example, C.D. Jones, M. Kaselj, R.N. Salvatore, W.J.le Noble J. Org. Chem. 1998, 63, 2758-2760.

The compounds of the present invention may contain asymmetrically substituted carbon atoms of R or S configuration. "R" and "S" are defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,13- 10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configurations are the same. If one configuration is more abundant than the other, the configuration of the chiral carbon atoms is represented by the configuration with the greater amount, preferably the enantiomeric excess is about 85-90%, more preferably about 95-99%, Further about 99% or more. Thus, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labeled compounds

The compounds of the present invention may exist in isotopically labeled or enriched form, containing one or more atoms that differ from the atomic mass and mass number most prevalent in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ³² P, ³⁵ S , ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Other isotopes containing these atoms and/or other atoms are also within the scope of the invention.

In another embodiment, the isotopically labeled compound contains a deuterium ( ^2H ), tritium ( ^3H ) or ^14C isotope. The isotopically labeled compounds of the present invention can be obtained using methods well known to those skilled in the art. These isotope-labeled compounds can be obtained by replacing non-labeled reagents with isotope-labeled reagents with reference to the examples and reaction diagrams of the present invention. In some cases, compounds can be treated with isotopic labeling reagents to replace atoms with isotopic atoms, for example, hydrogen with _deuterium can be exchanged through the action of a deuterated acid such as _D2SO4 / _D2O .

The isotope-labeled compound of the present invention can be used as a standard for BTK inhibitor pharmacodynamic binding tests. Compounds containing isotopes can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotope labeled parent compounds, and to study the metabolic fate of compounds in vivo (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). This type of metabolic study is important for the design of safe and effective therapeutic drugs, and can determine whether the active compound in the patient's body or the metabolite of the parent compound is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp .2-36, Academic press, London, 1985; Kato et al, J. Labeled Compounds. Radiopharmaceuticals, 36 (10): 927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88(1999)).

In addition, drugs containing non-reflective active isotopes, such as deuterated drugs, known as "heavy drugs", can be used to treat diseases and conditions associated with BTK activity. A compound in which the ratio of a certain isotope exceeds its natural abundance is called enrichment. Enriched amounts include, but are not limited to, for example, from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.

Stable isotope labeling of drugs can alter their physicochemical properties, such as pKa and liquid solubility. If isotope substitution affects regions involved in ligand-receptor interactions, these effects and changes may affect the pharmacodynamic response of the drug molecule. Stable isotope-labeled molecules have some physical properties that differ from unlabeled molecules, while the chemical and biological properties are the same, with one important difference: Because of the increased mass of the heavy isotope, any chemical bond involving a heavy isotope and another atom is stronger than a lighter isotope. Strong. Accordingly, the presence of isotopes at sites of metabolism or enzymatic transformation can slow down the reaction, potentially altering its pharmacokinetic characteristics or efficacy compared to non-isotopically labeled compounds.

In embodiment (1), the present invention provides compounds represented by formula (I):

Or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are respectively ^{Unsubstituted or substituted} by _{at least} ^one substituent _{independently} ^{selected from R} ,-(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t - and - (CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -; X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X' and N; Y is selected From CR ⁴ and N; R ¹ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl -C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl , CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O )OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(= NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S(O)R ^A1 R ^B1 , -S (O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P (O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is ^{Unsubstituted} or substituted ^by _at ^{least one} substituent independently ^{selected from R} and C _1-10 alkyl, wherein _the alkyl is unsubstituted or substituted by ^{at least} one substituent independently selected ^{from R} OR ^A3 , -C(O)NR ^A2 R ^B2 and C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from ^RX3 ; R ⁴ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^{A4 RB4} , -OR ^A4 and C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from ^RX4 ; R ⁵ is selected from hydrogen, Halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , -OR ^A5 , -C(O)R ^A5 , -C(=NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 , -C(O)NR ^A5 R ^B5 , -NR ^A5 C(O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR A5 R ^B5 , ^{-NR A5 C} (=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S(O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR A5 R ^B5 , ^-S (O)(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O )(OR ^A5 )(OR ^B5 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are respectively unsubstituted or independently selected from R ^X5 is substituted with a substituent; each R ^A0 and R ^B0 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _{3- 10Cycloalkyl} -C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _{1 -4} alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X0 ; Or each " ^RA0 and R ^B0 " together with the single or multiple atoms to which they are connected constitute a 4-12 membered heteroatom containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. Ring, _which ring may be optionally substituted by _{1 ,} ² or ^{3 R} ₁₀ alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _{1 -4} alkyl, heteroaryl and heteroaryl -C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted ^{by at} least one substituent independently selected from ^R , 4-12 membered heterocyclic ring with heteroatoms of sulfur, nitrogen and phosphorus, the ring may be optionally substituted by 1, 2 or 3 R ^X1 groups; each R ^A2 and R ^B2 are independently selected from hydrogen, C _{1 -10} alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, _{C 3-10 cycloalkyl} -C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl ^, heterocyclyl, aryl and heteroaryl are unsubstituted ^or substituted by at least one substituent independently selected from ^R The atoms constitute a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted by 1, 2 or 3 R ^X2 groups ;Each R ^A3 and R ^B3 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^{R A3} and R ^B3 "together with the single or multiple atoms connected to them form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may optionally _substituted by ₁ ^{, 2} _or ³ R _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, Heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one Substituted with ^substituents independently selected ^{from R} A 4-12 membered heterocyclic ring of phosphorus heteroatoms, which ring may be optionally substituted by 1, 2 or 3 R ^X4 groups; each R ^A5 and R ^B5 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C 3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl} , heterocyclyl, heterocyclyl-C _1-4 alkyl base, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are unsubstituted or substituted with ^at least one ^substituent independently selected from ^R 1 or 2 additional 4-12 membered heterocyclic rings with heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted by 1, 2 or 3 R ^X5 groups; each R ^C0 and R ^D0 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _{1- 4Alkyl} , heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which Alkyl, alkenyl, alkynyl, ^cycloalkyl , heterocyclyl, aryl and ^heteroaryl are unsubstituted or substituted with at least one substituent independently selected from ^R The single or multiple carbon atoms connected to them constitute a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally replaced by 1, 2 or 3 R ^X0 group substitution; each R ^E0 , R ^E1 and R ^E5 are independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , - C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ; each R ^X , R ^X , R ^X0 , R ^X1 , _R ^X2 , _R ^X3 _{, R} ^X4 _and ^R Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, halogen, CN, -NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O) NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) (=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -( CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are unsubstituted or substituted with at least one substituent independently selected from R ^Y ; each R ^a1 and R ^b1 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C 3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl ,} aryl, aromatic Base - C _1-4 alkyl, heteroaryl and heteroaryl - C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y ; or R ^a1 and R ^b1 together with the single or multiple atoms to which they are attached contain 0, 1 or 2 additional substituents independently selected from oxygen , a 4-12 membered heterocyclic ring with heteroatoms of sulfur, nitrogen and phosphorus, the ring may be optionally substituted by 1, 2 or 3 R ^Y groups; each R ^c1 and R ^d1 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl} , heterocyclyl, heterocycle base-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted by at least one substituent independently selected from R ^Y ; or R ^c1 and R ^d1 together with the single or multiple carbon atoms to which they are attached Constituting a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring may be optionally substituted by 1, 2 or 3 R ^Y groups; each R ^e1 is independently Selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S( O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ; each R ^Y is selected independently From C _1-10 alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl} , heterocyclyl, hetero Cyclic group-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P (O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P( O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)R ^a2 , -C(O) (CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, -C (O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ) , -C(=NR ^e2 )R ^a2 , -C(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C(= NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is unsubstituted or at least one independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di( C _1-10 alkyl) amino substituent substitution; each R ^a2 and R ^b2 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkyl Thio group, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl- C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio , cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _{1 -10} alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents substitution; or R ^a2 Together with R ^b2 and the single or multiple atoms connected to them, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be optional. 1 or 2 ground covers are independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy group, C _3-10 cycloalkoxy group, C _1-10 alkylthio group, C _3-10 cycloalkylthio group, amino group, C _1-10 alkylamino group, C _3-10 cycloalkylamino group and di(C _{1- 10} alkyl) amino substituent substitution; each R ^c2 and R ^d2 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 ring Alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio Base, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, Cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkene Base, C _2-10 alkynyl group, C _3-10 cycloalkyl group, hydroxyl group, C _1-10 alkoxy group, C _3-10 cycloalkoxy group, C _1-10 alkylthio group, C _3-10 cycloalkyl group Substituted with thio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents; or R ^c2 and R ^d2 together with single or multiple groups connected to them carbon atoms forming a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring may be optionally replaced by 1 or 2 independently selected from halogen, CN, C _{1- 10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkyl Substituents for thio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino; each R ^e2 is independently selected From hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 Cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _{3- 10} cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl , -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ; Each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4; and each u is independently selected from 0, 1, 2, 3, and 4.

In another embodiment (2), the present invention provides a compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ and the compound is represented by formula (II):

The definitions of Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are the same as those in formula (I).

In another embodiment (3), the invention provides a compound of embodiment (1), wherein Y is N, or a pharmaceutically acceptable salt thereof.

In another embodiment (4), the invention provides the compound of any one of embodiments (1)-(3) or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl and hetero Cyclic groups, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted by at least one substituent independently selected from ^R

、

和

，其是未被取代 的或被至少一個，獨立選自R^X的取代基取代。 In another embodiment (5), the invention provides a compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein Q is selected from

,

and

, which is unsubstituted or substituted by at least one substituent independently selected from ^R

和

，是未被取代的或被至少 一個，獨立選自R^X的取代基取代。 In another embodiment (6), the invention provides a compound of embodiment (5) or a pharmaceutically acceptable salt thereof, wherein Q is selected from

and

, is unsubstituted or substituted by at least one substituent independently selected from ^R

In another embodiment (7), the present invention provides the compound of any one of embodiments (1)-6) or a pharmaceutically acceptable salt thereof, wherein _the substituent ^R ₁₀ alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or replaced by at least one Substituted with substituents independently selected from R ^Y.

In another embodiment (8), the _present invention provides a compound of embodiment (7) or a pharmaceutically acceptable salt thereof, wherein _the substituent ^R ₁₀ Alkynyl, wherein each alkyl and alkynyl is unsubstituted or substituted with at least one substituent independently selected from R ^Y.

In another embodiment (9), the present invention provides a compound of embodiment (8) or a pharmaceutically acceptable salt thereof, wherein the substituent ^R R ^Y is F or OH.

In another embodiment (10), the invention provides a compound of any one of embodiments (1)-(9), or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from C _1-10 alkyl and C _3-10 cycloalkyl, wherein the alkyl and cycloalkyl are respectively unsubstituted or substituted by at least one substituent independently selected from R ^X1 .

In another embodiment (11), the invention provides a compound of embodiment (10), or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted Substituted with at least one substituent independently selected from R ^X1 .

In another embodiment (12), the present invention provides a compound of embodiment (11) or a pharmaceutically acceptable salt thereof, wherein ^R1 is methyl, wherein the substituent ^RX1 of the methyl group is selected from OH,

部分的結構 選自

In another embodiment (13), the present invention provides a compound of any one of embodiments (1)-(12) or a pharmaceutically acceptable salt thereof, wherein formula (I) or formula (II)

The structure of the part is selected from

部分的結構選自

In another embodiment (14), the present invention provides a compound of embodiment (13) or a pharmaceutically acceptable salt thereof, wherein formula (I) or formula (II)

The structure of the part is selected from

部分的結構選自

In another embodiment (15), the present invention provides a compound of embodiment (14) or a pharmaceutically acceptable salt thereof, wherein formula (I) or formula (II)

The structure of the part is selected from

In another embodiment (16), the invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (15), wherein X ¹ , X ² , X ³ and X ⁴ are independently Selected _from ^{CR X ' and} N ^, _{where R}

部分的結 構選自

和

In another embodiment (17), the present invention provides a compound of any one of embodiments (1) to (16) or a pharmaceutically acceptable salt thereof, wherein of formula (I) or formula (II)

The structure of the part is selected from

and

部分的結構選自

In another embodiment (18), the present invention provides a compound of embodiment (17) or a pharmaceutically acceptable salt thereof, wherein formula (I) or formula (II)

The structure of the part is selected from

部分的結構選自

In another embodiment (19), the present invention provides a compound of embodiment (18) or a pharmaceutically acceptable salt thereof, wherein formula (I) or formula (II)

The structure of the part is selected from

In another embodiment (20), the invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments (16) to (19), wherein ^R , CN, methyl, methoxy and cyclopropyl.

In another embodiment (21), the invention provides a compound of embodiment (20), or a pharmaceutically acceptable salt thereof, wherein ^R

In another embodiment (22), the invention provides a compound of embodiment (21) or a pharmaceutically acceptable salt thereof, wherein ^R F is preferred.

部分的結構選自

和

；優選

部分的結構選自

；進一步優選，

部分的結構選自

和

；更進一步優選，

部分的 結構選自

In another embodiment (23), the present invention provides a compound of embodiment (18) or a pharmaceutically acceptable salt thereof, wherein of formula (I) or formula (II)

The structure of the part is selected from

and

;Preferred

The structure of the part is selected from

; Further preferred,

The structure of the part is selected from

and

;More preferably,

The structure of the part is selected from

In another embodiment (24), the invention provides a compound of any one of embodiments (1) to (23), or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a chemical bond, -(CR ^{COR D0} ) _u O(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -and-(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -.

In another embodiment (25), the invention provides a compound of embodiment (24), or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of chemical bond, -O-, -S- and -C(O)N( R ^A0 )-.

In another embodiment (26), the invention provides a compound of embodiment (25), or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a chemical bond and -O-.

In another embodiment (27), the invention provides a compound of embodiment (26), or a pharmaceutically acceptable salt thereof, wherein L is -O-.

In another embodiment (28), the invention provides a compound according to any one of embodiments (1) to (27), or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from halogen, C _1-10 alkyl , C _3-10 cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are respectively unsubstituted or substituted by at least one substituent independently selected from R ^X5 .

In another embodiment (29), the invention provides a compound of embodiment (28), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from F, phenyl and pyridyl, wherein phenyl and pyridyl are respectively Unsubstituted or substituted by at least one substituent independently selected from ^RX5 .

In another embodiment (30), the invention provides a compound of embodiment (29), or a pharmaceutically acceptable salt thereof, wherein ^R5 is phenyl, wherein phenyl is unsubstituted or substituted by at least one, independently Substituted with a substituent selected from R ^X5 .

In another embodiment (31), the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments (28) to ( ₃₀ ), wherein ^R C _2-10 alkenyl, C _2-10 alkynyl, C 3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl} , heterocyclyl, heterocyclyl-C _1-4 alkyl base, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 and -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and hetero Aryl groups are unsubstituted or substituted with at least one substituent independently selected from R ^Y.

In another embodiment (32), the invention provides a compound of embodiment (31), or a pharmaceutically acceptable salt thereof, wherein ^R

In another embodiment (33), the invention provides a compound of embodiment (32), or a pharmaceutically acceptable salt thereof, wherein R ^X5 is selected from halogen, preferably R ^X5 is F.

In another embodiment (34), the invention provides a compound of embodiment (29), or a pharmaceutically acceptable salt thereof, wherein ^R5 is phenyl, wherein phenyl is unsubstituted or substituted by at least one, independently Substituted with a substituent selected from F and methoxy; preferably phenyl is unsubstituted or substituted with at least one substituent independently selected from F; or ^R5 is pyridyl, wherein pyridyl is unsubstituted or substituted by Substituted with at least one substituent independently selected from F.

In another embodiment (35), the invention provides a compound of embodiment (34), or a pharmaceutically acceptable salt thereof, wherein ^R5 is pyridyl, wherein pyridyl is unsubstituted.

In another embodiment (36), the invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (35), wherein ^R5 is selected from F, phenyl,

和

In another embodiment (37), the invention provides a compound of embodiment (36), or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from phenyl,

and

和

In another embodiment (38), the invention provides a compound of embodiment (37), or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from

and

部分的結構選自

和

；優選

部分的結構選自

和

；進一步優選，

部分的結構選自是

In another embodiment (39), the invention provides a compound of embodiment (23), or a pharmaceutically acceptable salt thereof, wherein

The structure of the part is selected from

and

;Preferred

The structure of the part is selected from

and

; Further preferred,

The structure of the part is selected from

In another embodiment (40), the invention provides a compound of any one of embodiments (1)-(39), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from hydrogen, halogen, C _1-10 Alkyl, -OR ^A2 , -C(O)NR ^A2 R ^B2 and CN.

In another embodiment (41), the invention provides a compound of embodiment (40), or a pharmaceutically acceptable salt thereof, wherein R ^A2 in -OR ^A2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl and C _3-10 cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are respectively unsubstituted or substituted by at least one substituent independently selected from R ^X2 .

In another embodiment (42), the invention provides a compound of any one of embodiments (40)-(41), or a pharmaceutically acceptable salt thereof, wherein R ^X2 is selected from deuterium and halogen.

In another embodiment (43), the invention provides a compound of any one of embodiments (1)-(42), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from hydrogen, F, Cl, methyl , ethyl, methoxy, ethoxy, -C(O)NH ₂ , CN, OH,

In another embodiment (44), the invention provides a compound of embodiment (43), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from hydrogen, F, Cl, CN, methoxy and ethoxy.

In another embodiment (45), the invention provides a compound of embodiment (44), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from hydrogen, CN, methoxy and ethoxy.

In another embodiment (46), the invention provides a compound of embodiment (45), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from the group consisting of hydrogen, methoxy and ethoxy.

In another embodiment (47), the invention provides a compound of embodiment (46), or a pharmaceutically acceptable salt thereof, wherein ^R2 is selected from methoxy and ethoxy.

In another embodiment (48), the invention provides a compound of any one of embodiments (1) to (47), or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are independently selected from hydrogen, C _{1 -10} alkyl and halogen.

In another embodiment (49), the invention provides a compound of embodiment (48), or a pharmaceutically acceptable salt thereof, wherein ^R3 is hydrogen.

In another embodiment (50), the invention provides a compound of embodiment (48), or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen.

和其藥學上可接受的鹽。 In another embodiment (51), the invention provides a compound selected from:

and pharmaceutically acceptable salts thereof.

In another embodiment (52), the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments (1) to (51) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable salt. carrier.

In another embodiment (53), the present invention provides a method of treating, ameliorating, or preventing a condition responsive to inhibition of BTK, comprising administering to an individual in need thereof an effective amount of any of embodiments (1)-(51) The compound of the item, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally used in combination with a second therapeutic agent.

In another embodiment (54), the present invention provides a compound of any one of embodiments (1) to (51) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating abnormal cell proliferation diseases. use.

<I’> Some embodiments can also be described as follows: In embodiment <1>, the present invention provides compounds represented by formula <I'>:

<I'>

Or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are respectively ^{Unsubstituted or substituted} by _{at least} ^one substituent _{independently} ^{selected from R} ,-(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t -and-(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -; X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X and N; R ¹ is selected From hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl , heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , - NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O)OR ^A1 , -OC( O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , - OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S(O)R ^A1 R ^B1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O )(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P(O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, respectively, is unsubstituted or is substituted by at least Substituted ^with _a ^{substituent independently} _selected ^{from R} or substituted ^by _at ^{least one} substituent independently ^selected _from ^{R Is} unsubstituted _or substituted ^{by at least} one substituent independently selected _from ^R , wherein the alkyl group is unsubstituted _or substituted by ^at _{least one} substituent independently selected from ^R ₁₀ alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _{1 -4} alkyl, heteroaryl, heteroaryl -C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , -OR ^A5 , -C(O) ^RA5 , -C(=NR ^E5 ) R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 , -C(O)NR ^A5 R ^B5 , -NR ^A5 C(O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C( O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S(O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S (O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O)(OR ^A5 )(OR ^B5 ), where each alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent independently selected from R ^X ; each R ^A0 , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^B0 , R ^B1 , R ^B2 , R ^B3 , R ^B4 and R ^B5 are independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkyne Base, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 Alkyl, Heteroaryl and Heteroaryl-C _1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or ^{Substituted by at least one substituent independently selected from R RB4} " or " ^RA5 and ^RB5 " together with the single or multiple atoms to which they are attached constitute a 4-12 member containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus ^Heterocyclic ring, which _ring may be optionally substituted by 1 _, ² or ³ R Base, C _2-10 alkynyl, C _3-10 cycloalkyl, C ₃₁₀ cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl -C _1-4 alkyl, heteroaryl and heteroaryl -C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is ^{Unsubstituted} or substituted by ^at least one substituent independently selected from ^R and nitrogen heteroatoms, which ring may be optionally substituted by 1, 2 or 3 ^RX groups; each ^RE0 , ^RE1 and ^RE5 is independently selected from hydrogen, deuterium, _{C -10} alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 _R ^b1 and _-S (O _{) r} NR ^a1 R ^b1 _; each ^R Cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl , heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t CR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N-CR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^b1 ) _t CC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S( O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^e1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where each alkyl, alkenyl, alkynyl group , cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted by at least one substituent independently selected from R ^Y ; each R ^a1 and R ^b1 are independently selected from hydrogen, deuterium, C _{1 -10} alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, _{C 3-10 cycloalkyl} -C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl and heteroaryl are unsubstituted or substituted by at least one substituent independently selected from R ^Y ; or R ^a1 and R ^b1 together with the single or multiple atoms to which they are connected contain 0 , 1 or 2 additional 4-12 membered heterocyclic rings with heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted by 1, 2 or 3 R ^Y groups; each R ^c1 and R ^d1 are independently selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y ; or R ^c1 and R ^d1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally replaced by 1, 2 or 3 R ^Y groups are substituted; each R ^e1 is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN , NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C (O)NR ^a2 R ^b2 ; each R ^Y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 ring Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O) R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O) NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, -C(O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O) OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ) , -C(=NR ^e2 )R ^a2 , -C( =NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where each alkyl, alkenyl, and alkynyl groups , cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _{1 -10} alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^a2 and R ^b2 are independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl Oxygen group, C _1-10 alkylthio group, C _3-10 cycloalkylthio group, C _1-10 alkylamino group, C _3-10 cycloalkylamino group, di(C _1-10 alkyl) amino group, heterocyclyl group, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl , cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one, Such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _{1 -10} alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di (C _1-10 alkyl) amino substituent substitution; or R ^a2 and R ^b2 together with the single or multiple atoms to which they are connected contain 0, 1 or 2 additional independently selected from oxygen, sulfur, nitrogen and A 4-12 membered heterocyclic ring of phosphorus heteroatoms, which ring may be optionally replaced by 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _{1- 10} alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^c2 and R ^d2 are independently selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 ring Alkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl , heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkyne group, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted by at least one Independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 Cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino Substituent substitution; or R ^c2 and R ^d2 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, The ring may optionally be replaced by 1 or 2 independently selected from the group consisting of halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and Substituted with di(C _1-10 alkyl)amino substituents; each R ^e2 is independently selected from hydrogen, deuterium, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 Cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 ring Alkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N (C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4 ;Each u is independently selected from 0, 1, 2, 3 and 4.

In another embodiment <2>, the present invention provides the compound of embodiment <1> or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl and heterocyclyl, wherein cycloalkyl and Heterocyclyl groups are respectively unsubstituted or substituted by at least one substituent independently selected from ^R

In another embodiment <3>, the present invention provides the compound of embodiment <2> or a pharmaceutically acceptable salt thereof, wherein Q is selected from cyclohexyl and tetrahydropyran, wherein cyclohexyl and tetrahydropyran are respectively is unsubstituted or substituted with at least one substituent independently selected from ^R

In another embodiment <4>, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments <1> to <3>, wherein R ¹ is selected from C _1-10 alkyl and C _3-10 cycloalkyl, wherein the alkyl and cycloalkyl are respectively unsubstituted or substituted by at least one substituent independently selected from ^R

In another embodiment <5>, the present invention provides the compound of embodiment <4> or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-10 alkyl group, wherein the alkyl group is unsubstituted or substituted Substituted with at least one substituent independently selected from ^R

In another embodiment <6>, the present invention provides the compound of embodiment <5>, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein the methyl is substituted by ^RX .

In another embodiment <7>, the present invention provides the compound of embodiment <6>, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein the methyl is substituted by OH.

In another embodiment <8>, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments <1> to <7>, wherein X ¹ , X ² , X ³ and X ⁴ are selected from ^{From CR} _{_}

是

In another embodiment <9>, the present invention provides the compound of embodiment <8> or a pharmaceutically acceptable salt thereof, wherein the substructure of formula <I'> is <II'>

yes

In another embodiment <10>, the present invention provides the compound of embodiment <9> or a pharmaceutically acceptable salt thereof, wherein R ^X is selected from hydrogen, F, Cl, CN and methyl.

In another embodiment <11>, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments <1> to <10>, wherein L is selected from -(CR ^C1 R ^D1 ) _u O (CR ^C1 R ^D1 ) _t -, -(CR ^C1 R ^D1 ) _u S(CR ^C1 R ^D1 ) _t - and -(CR ^C1 R ^D1 ) _u C(O)NR ^A1 (CR ^C1 R ^D1 ) _t -.

In another embodiment <12>, the present invention provides the compound of embodiment <11> or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R ^A1 )-.

In another embodiment <13>, the present invention provides the compound of embodiment <12>, wherein L is -O-, or a pharmaceutically acceptable salt thereof.

In another embodiment <14>, the present invention provides the compound of any one of embodiments <1> to <13>, or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from an aryl group and a heteroaryl group, wherein Aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from ^R

In another embodiment <15>, the present invention provides the compound of embodiment <14>, or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from an aryl group, wherein the aryl group is unsubstituted or substituted by ^R .

In another embodiment <16>, the present invention provides the compound of embodiment <15>, or a pharmaceutically acceptable salt thereof, wherein the phenyl group is unsubstituted or substituted by halogen.

In another embodiment <17>, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments <1> to <16>, wherein R ² is selected from hydrogen, deuterium, halogen, C _{1 -10} alkyl and CN.

In another embodiment <18>, the present invention provides the compound of embodiment <17>, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F and CN.

In another embodiment <19>, the present invention provides a compound or a pharmaceutically acceptable salt thereof in any one of embodiments <1> to <18>, wherein R ³ and R ⁴ are independently selected from hydrogen, deuterium, C _1-10 alkyl and halogen.

In another embodiment <20>, the present invention provides the compound of embodiment <19>, or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

In another embodiment <21>, the present invention provides the compound of embodiment <20>, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

In another embodiment <22>, the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments <1> to <21> or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable salt. carrier.

In another embodiment <23>, the present invention provides a method for treating, improving or preventing a condition responsive to inhibition of BTK, comprising administering an effective amount of any one of embodiments <1> to <21> to an individual in need thereof. The compound of the item, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally used in combination with a second therapeutic agent.

In another embodiment <24>, the present invention provides the compound of any one of embodiments <1> to <21> or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating abnormal cell proliferation diseases. use.

Some embodiments can also be described as follows: In embodiment [1], the present invention provides compounds represented by formula [I″]:

Or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are respectively ^{Unsubstituted or substituted} by _{at least} ^one substituent _{independently} ^{selected from R} ,-(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t - and - (CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -; X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X and N; Y is selected from CR ⁴ and N; R ¹ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O) OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , - NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S(O)R ^A1 R ^B1 , -S( O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P( O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is respectively ^Substituted or ^{substituted by} _at ^{least one} substituent independently selected ^{from R} C _1-10 alkyl, wherein _the alkyl is unsubstituted or ^substituted by ^{at least} one substituent independently selected from ^{R A3} , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from R ^X ; R ⁴ is selected from hydrogen, halogen, CN , NO ₂ , -NR ^{A4 RB4} , -OR ^A4 , C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from ^RX ; R ⁵ is selected from hydrogen, halogen , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, hetero Cyclic group - C _1-4 alkyl, aryl, aryl - C _1-4 alkyl, heteroaryl, heteroaryl - C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , - OR ^A5 , -C(O)R ^A5 , -C(=NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 ,- C(O)NR ^A5 R ^B5 , -NR ^A5 C(O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S(O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 ) NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O) (OR ^A5 )(OR ^B5 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is individually unsubstituted or independently selected from ^R Substituted with substituents; each R ^A0 , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^B0 , R ^B1 , ^RB2 , ^RB3 , ^RB4 and ^RB5 are independently selected from hydrogen, C _{1- 10} alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4} alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl are unsubstituted ^or substituted with ^{at least one} substituent independently selected ^{from R RB2} ", " ^RA3 and ^RB3 ", " ^RA4 and ^RB4 " or " ^RA5 and ^RB5 " together with the single or multiple atoms to which they are connected contain 0, 1 or 2 additional independent options. A 4-12 membered heterocyclic ring composed of heteroatoms of oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted by 1, 2 or 3 R ^X groups; each R ^C0 and R ^D0 are independently selected from hydrogen, Halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and ^heteroaryl are unsubstituted or substituted by ^at least one substituent independently selected from ^R The carbon atoms form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted by 1, 2 or 3 R ^X groups; each R ^E0 , R ^E1 and R ^E5 are independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , - C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ; each R ^X is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C 3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl ,} aryl, aromatic Base-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N -OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S( O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S (O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S (O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ) , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y ; each R ^a1 and R ^b1 are independently selected from hydrogen, _{C 1-10} alkyl, C 2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl base, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted by at least one substituent independently selected from R ^Y ; or R ^a1 and R ^b1 together with them The connected single or multiple atoms constitute a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally replaced by 1, 2 or 3 substituted by R ^Y groups; each R ^c1 and R ^d1 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl -C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R ^Y group substitution; or R ^c1 and R ^d1 together with the single or multiple carbon atoms connected to them form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring can Optionally substituted by 1, 2 or 3 R ^Y groups; each R ^e1 is independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _{1 -4} alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ; each R ^Y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl , C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl Base -C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , - OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C (O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C (O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, -C(O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , - NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ) , -C(=NR ^e2 ) R ^a2 , -C(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where each alkyl group , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _{2 -10} alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 ring Alkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^a2 and R ^b2 are independently selected from hydrogen, C _1-10 Alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _{3 -10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, Heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl radical, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or Be at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, Hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 ring Alkylamino and di(C _1-10 alkyl)amino substituents are substituted; or R ^a2 and R ^b2 together with the single or multiple atoms to which they are connected contain 0, 1 or 2 additional independently selected from oxygen, A 4-12 membered heterocyclic ring with heteroatoms of sulfur, nitrogen and phosphorus, the ring may be optionally substituted by 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino , C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^c2 and R ^d2 are independently selected from hydrogen, halogen, C _1-10 alkyl Base, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _{3- 10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, hetero Cyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl , alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or At least one is independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _{3 -10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl) Substituent substitution of the amino group; or R ^c2 and R ^d2 together with the single or multiple carbon atoms to which they are attached constitute a 3-12 member containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen. Ring, which ring can be optionally replaced by 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl , C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkyl Substituted with amino and di(C _1-10 alkyl)amino substituents; each R ^e2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 Cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 ring Alkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N (C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4 ;Each u is independently selected from 0, 1, 2, 3 and 4.

In another embodiment [2], the present invention provides the compound of embodiment [1] or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ and the compound is represented by formula [II″]:

The definitions of Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are the same as those of formula [I”].

In another embodiment [3], the present invention provides the compound of any one of embodiments [1]-[2] or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl and hetero Cyclic groups, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted by at least one substituent independently selected from ^R

，是未被取代的或 被至少一個，獨立選自R^X的取代基取代。 In another embodiment [4], the present invention provides the compound of embodiment [3] or a pharmaceutically acceptable salt thereof, wherein Q is selected from

, is unsubstituted or substituted by at least one substituent independently selected from ^R

In another embodiment [5], the present invention provides the compound of any one of embodiments [1]-[4] or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from C _1-10 alkyl and C _3-10 cycloalkyl, wherein the alkyl and cycloalkyl are respectively unsubstituted or substituted by at least one substituent independently selected from ^R

In another embodiment [6], the present invention provides the compound of embodiment [5] or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted Substituted with at least one substituent independently selected from ^R

In another embodiment [7], the present invention provides the compound of embodiment [6] or a pharmaceutically acceptable salt thereof, wherein ^R1 is methyl, wherein the methyl is replaced by OH, CN and

In another embodiment [8], the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments [1] to [7], wherein X ¹ , X ² , X ³ and X ⁴ are independently Selected from CR ^X and N, _where ^R

In another embodiment [9], the present invention provides a compound of any one of embodiments [1] to [8] or a pharmaceutically acceptable salt thereof, wherein formula [I″] or formula [II″] Substructure [III”] is selected from

In another embodiment [10], the present invention provides a compound of embodiment [9], or a pharmaceutically acceptable salt thereof, wherein ^R

In another embodiment [11], the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments [1] to [10], wherein L is selected from -(CR ^C1 R ^D1 ) _u O (CR ^C1 R ^D1 ) _t -, -(CR ^C1 R ^D1 ) _u S(CR ^C1 R ^D1 ) _t - and -(CR ^C1 R ^D1 ) _u C(O)NR ^A1 (CR ^C1 R ^D1 ) _t -.

In another embodiment [12], the present invention provides the compound of embodiment [11] or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R ^A1 )-.

In another embodiment [13], the present invention provides a compound of embodiment [12], wherein L is -O-, or a pharmaceutically acceptable salt thereof.

In another embodiment [14], the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments [1] to [13], wherein ^R5 is selected from aryl and heteroaryl, wherein Aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from ^R

In another embodiment [15], the present invention provides the compound of embodiment [14] or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from phenyl and pyridyl, wherein phenyl and pyridyl are respectively un Substituted or substituted by at least one substituent independently selected from ^R

In another embodiment [16], the present invention provides a compound of embodiment [15], or a pharmaceutically acceptable salt thereof, wherein ^R

In another embodiment [17], the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments [1] to [16], wherein R ² is selected from hydrogen, halogen, C _1-10 Alkyl, -OR ^A2 , -C(O)NR ^A2 R ^B2 and CN.

In another embodiment [18], the present invention provides a compound of embodiment [17] or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F, Cl, methyl, -OR ^A2 , -C( O)NR ^A2 R ^B2 and CN. hydrogen, F, Cl, methyl, methoxy, -C(O)NH ₂ and CN.

In another embodiment [19], the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments [1] to [18], wherein R ³ and R ⁴ are independently selected from hydrogen, C _{1 -10} alkyl and halogen.

In another embodiment [20], the present invention provides a compound of embodiment [19], or a pharmaceutically acceptable salt thereof, wherein ^R3 is hydrogen.

In another embodiment [21], the present invention provides a compound of embodiment [19], or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen.

In another embodiment [22], the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments [1] to [21] or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable salt. carrier.

In another embodiment [23], the present invention provides a method of treating, ameliorating or preventing a condition responsive to inhibition of BTK, comprising administering to an individual in need thereof an effective amount of any of embodiments [1]-[21] The compound of the item, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally used in combination with a second therapeutic agent.

In another embodiment [24], the present invention provides a compound of any one of embodiments [1] to [21] or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating abnormal cell proliferation diseases. use.

Some embodiments can also be described as follows: In embodiment (i), the present invention provides compounds represented by formula (I'''):

Or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are respectively ^{Unsubstituted or substituted} by _{at least} ^one substituent _{independently} ^{selected from R} ,-(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -,-(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t - and - (CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -; X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X and N; Y is selected from CR ⁴ and N; R ¹ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O) OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , - NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S(O)R ^A1 R ^B1 , -S( O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P( O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is respectively ^Substituted or ^{substituted by} _at ^{least one} substituent independently selected ^{from R} C _1-10 alkyl, wherein _the alkyl is unsubstituted or ^substituted by ^{at least} one substituent independently selected from ^{R A3} , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from R ^X ; R ⁴ is selected from hydrogen, halogen, CN , NO ₂ , -NR ^{A4 RB4} , -OR ^A4 , C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from ^RX ; R ⁵ is selected from hydrogen, halogen , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, hetero Cyclic group - C _1-4 alkyl, aryl, aryl - C _1-4 alkyl, heteroaryl, heteroaryl - C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , - OR ^A5 , -C(O)R ^A5 , -C(=NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 ,- C(O)NR ^A5 R ^B5 , -NR ^A5 C(O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^EB )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S(O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 ) NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O) (OR ^A5 )(OR ^B5 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is individually unsubstituted or independently selected from ^R Substituted with substituents; each R ^A0 , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^B0 , R ^B1 , ^RB2 , ^RB3 , ^RB4 and ^RB5 are independently selected from hydrogen, C _{1- 10} alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4} alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl are unsubstituted ^or substituted with ^{at least one} substituent independently selected ^{from R RB2} ", " ^RA3 and ^RB3 ", " ^RA4 and ^RB4 " or " ^RA5 and ^RB5 " together with the single or multiple atoms to which they are connected contain 0, 1 or 2 additional independent options. A 4-12 membered heterocyclic ring composed of heteroatoms of oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted by 1, 2 or 3 R ^X groups; each R ^C0 and R ^D0 are independently selected from hydrogen, Halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and ^heteroaryl are unsubstituted or substituted by ^at least one substituent independently selected from ^R The carbon atoms form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted by 1, 2 or 3 R ^X groups; each R ^E0 , R ^E1 and R ^E5 are independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , - C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ; each R ^X is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C 3-10 cycloalkyl, C _3-10 cycloalkyl- _{C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl ,} aryl, aromatic Base-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N -OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S( O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S (O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S (O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ) , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y ; each R ^a1 and R ^b1 are independently selected from hydrogen, _{C 1-10} alkyl, C 2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl base, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted by at least one substituent independently selected from R ^Y ; or R ^a1 and R ^b1 together with them The connected single or multiple atoms constitute a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally replaced by 1, 2 or 3 substituted by R ^Y groups; each R ^c1 and R ^d1 are independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl -C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R ^Y group substitution; or R ^c1 and R ^d1 together with the single or multiple carbon atoms connected to them form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring can Optionally substituted by 1, 2 or 3 R ^Y groups; each R ^e1 is independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _{1 -4} alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ; each R ^Y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl , C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl Base -C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , - OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ) , -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C (O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C (O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, -C(O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , - NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ) , -C(=NR ^e2 ) R ^a2 , -C(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where each alkyl group , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _{2 -10} alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 ring Alkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^a2 and R ^b2 are independently selected from hydrogen, C _1-10 Alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _{3 -10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, Heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl radical, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or Be at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, Hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 ring Alkylamino and di(C _1-10 alkyl)amino substituents are substituted; or R ^a2 and R ^b2 together with the single or multiple atoms to which they are connected contain 0, 1 or 2 additional independently selected from oxygen, A 4-12 membered heterocyclic ring with heteroatoms of sulfur, nitrogen and phosphorus, the ring may be optionally substituted by 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino , C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^c2 and R ^d2 are independently selected from hydrogen, halogen, C _1-10 alkyl Base, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _{3- 10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, hetero Cyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl , alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are unsubstituted or At least one is independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _1-10 alkoxy, C _{3 -10} cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl) Substituent substitution of the amino group; or R ^c2 and R ^d2 together with the single or multiple carbon atoms to which they are attached constitute a 3-12 member containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen Ring, which ring can be optionally replaced by 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl , C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkyl Substituted with substituents of amino and di(C _1-10 alkyl)amino; each R ^e2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 Cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 ring Alkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N (C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4 ; Each u is independently selected from 0, 1, 2, 3 and 4.

In another embodiment (ii), the invention provides a compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ and the compound is represented by formula (II'''):

The definitions of Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are the same as those of formula (I''').

In another embodiment (iii), the invention provides a compound of any one of embodiments (i)-(ii), or a pharmaceutically acceptable salt thereof, wherein Q is selected from C _3-10 cycloalkyl and hetero Cyclic groups, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted by at least one substituent independently selected from ^R

，其是未被取代的 或被至少一個，獨立選自R^X的取代基取代。 In another embodiment (iv), the invention provides a compound of embodiment (iii), or a pharmaceutically acceptable salt thereof, wherein Q is selected from

, which is unsubstituted or substituted by at least one substituent independently selected from ^R

In another embodiment (v), the invention provides a compound of any one of embodiments (i)-(iv), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from C _1-10 alkyl and C _3-10 cycloalkyl, wherein the alkyl and cycloalkyl are respectively unsubstituted or substituted by at least one substituent independently selected from R ^X.

In another embodiment (vi), the invention provides a compound of embodiment (v), or a pharmaceutically acceptable salt thereof, wherein ^R1 is _C1-10 alkyl, wherein the alkyl is unsubstituted or Substituted with at least one substituent independently selected from ^R

取代。 In another embodiment (vii), the invention provides a compound of embodiment (vi), or a pharmaceutically acceptable salt thereof, wherein ^R1 is methyl, wherein methyl is replaced by OH, CN and

replace.

In another embodiment (viii), the invention provides a compound of any one of embodiments (i)-(vii), or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ³ and X ⁴ are independently _{Selected from} ^{CR X and} N ^{, where} _R

In another embodiment (ix), the invention provides a compound of any one of embodiments (i)-(viii) or a pharmaceutically acceptable salt thereof, wherein formula (I''') or formula (II ''') substructure

In another embodiment (x), the invention provides a compound of embodiment (ix), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from hydrogen, F, Cl, Br, CN, methyl, methoxy and cyclopropyl.

In another embodiment (xi), the invention provides a compound of any one of embodiments (i)-(x), or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR ^C0 R ^D0 ) _u O (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t - and -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -.

In another embodiment (xii), the invention provides a compound of embodiment (xi), or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R ^A1 )-.

In another embodiment (xiii), the invention provides a compound of embodiment (xii), or a pharmaceutically acceptable salt thereof, wherein L is -O-.

In another embodiment (xiv), the invention provides a compound of any one of embodiments (i)-(xiii), or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from aryl and heteroaryl, wherein Aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from ^R

In another embodiment (xv), the invention provides a compound of embodiment (xiv) or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from phenyl and pyridyl, wherein phenyl and pyridyl are respectively unsubstituted or substituted by R ^X substituent.

In another embodiment (xvi), the invention provides a compound of embodiment (xv), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from the group consisting of halogen and methoxy.

In another embodiment (xvii), the invention provides a compound of any one of embodiments (i)-(xvi), or a pharmaceutically acceptable salt thereof, wherein ^R is selected from hydrogen, halogen, C _1-10 Alkyl, -OR ^A2 , -C(O)NR ^A2 R ^B2 and CN.

In another embodiment (xviii), the invention provides a compound of embodiment (xvii) or a pharmaceutically acceptable salt thereof, wherein R ^A2 in -OR ^A2 is independently selected from hydrogen, C _1-10 alkyl, C _{2 -10} alkenyl and C _3-10 cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are respectively unsubstituted or substituted by at least one substituent independently selected from ^R

In another embodiment (xix), the invention provides a compound of any one of embodiments (xvii)-(xviii), or a pharmaceutically acceptable salt thereof, wherein R ^is selected from hydrogen, F, Cl, methyl , ethyl, methoxy, ethoxy, -C(O)NH ₂ , CN, OH,

In another embodiment (xx), the invention provides a compound of any one of embodiments (i)-(xix), or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are independently selected from hydrogen, C _{1 -10} alkyl and halogen.

In another embodiment (xxi), the invention provides a compound of embodiment (xx), or a pharmaceutically acceptable salt thereof, wherein ^R3 is hydrogen.

In another embodiment (xxii), the invention provides a compound of embodiment (xxi), or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen.

In another embodiment (xxiii), the invention provides a pharmaceutical composition comprising a compound of any one of embodiments (i)-(xxii) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable salt carrier.

In another embodiment (xxiv), the present invention provides a method of treating, ameliorating, or preventing a condition responsive to inhibition of BTK, comprising administering to an individual in need thereof an effective amount of any of embodiments (i)-(xxii)). A compound of one of the invention, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

In another embodiment (xxv), the present invention provides a compound of any one of embodiments (i) to (xxii) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating abnormal cell proliferation diseases. use.

In another aspect, the invention provides a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and instructions including one or more of the following information: the disease state in which the ingredient is used, storage information of the ingredient, Dosage information and instructions on how to use the ingredients. In a special variant, the kit contains the compound in multi-dose form.

In another aspect, the invention provides articles of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and packaging materials. In one variation, the packaging material includes a container. In a particular variation, the container includes a label indicating one or more of the following: the disease state in which the compound is intended, storage information, dosage information, and/or instructions on how to use the compound. In another variation, the article of manufacture includes multiple dosage forms of the compound.

In another aspect, the invention provides a method of treatment comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method of inhibiting BTK by contacting a compound disclosed herein, or a pharmaceutically acceptable salt thereof, with BTK.

In another aspect, the invention provides a method of inhibiting BTK, comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to appear in an individual's body to inhibit BTK activity in the body.

In another aspect, the invention provides a method of inhibiting BTK, comprising administering a first compound to an individual, which compound is converted into a second compound in vivo, wherein the second compound inhibits BTK activity in vivo, and the second compound is the above implementation Compounds and variants of any of the schemes.

In another aspect, the invention provides a method of treating a disease state, wherein BTK activity is responsible for the pathology and/or symptoms of the disease state, the method comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutical thereof to the disease state. On the acceptable salt, occurs in the individual body.

In another aspect, the invention provides a method of treating a disease state in which BTK activity is responsible for the pathology and/or symptoms of the disease state, the method comprising administering to a subject a first compound that is converted in vivo to a second compound , wherein the second compound inhibits BTK activity in vivo. It is worth noting that the compounds described in the present invention can be compounds before or after conversion.

In variations of each of the above methods, the disease state is selected from the group consisting of: cancerous proliferative disease (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, renal, kidney, ovary, Prostate, colorectal, epidermal, esophageal, testicular, gynecological, or thyroid cancer); noncancerous proliferative diseases (such as benign skin hyperplasia (such as psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney Disease; pain; prevention of blastocyst implantation; treatment of diseases related to vasculogenesis or vasculogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases Such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer , lung, pancreatic, prostate, colon, and epidermoid carcinomas); asthma; neutrophil chemotaxis (e.g., reperfusion injury and inflammatory arthritis in myocardial infarction and stroke); septic shock; T cells mediated diseases in which immunosuppression is valuable (e.g., prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratogenesis in response to mixtures of growth factors Cells; chronic obstructive pulmonary disease (COPD) and other diseases.

In another aspect, the present invention provides a method of treating disease states in which mutations in the BTK gene are responsible for the pathology and/or symptoms of the disease state, such as melanoma, lung cancer, colon cancer, and other types of tumors.

In another aspect, the invention relates to the use of compounds and variants of any of the above embodiments as a medicament. In another aspect, the invention relates to the use of compounds and variants of any of the above embodiments for the preparation of a BTK-inhibiting medicament.

In another aspect, the invention relates to the use of the compounds and variants of any of the above embodiments for the preparation of a medicament for the treatment of pathological and/or symptomatic disease states resulting from BTK activity.

Administration and pharmaceutical compositions

Generally, the compounds of the present invention will be administered in a therapeutically effective amount by any common and acceptable means known in the art, alone or in combination with one or more therapeutic agents. The therapeutically effective amount can vary widely, depending on the severity of the disease, age and relative health of the subject, the potency of the compound used, and other factors known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the dosage required will vary depending on the mode of administration, the specific condition to be treated and the desired effect.

Generally, satisfactory results are achieved with a daily dose of 0.001 to 100 mg/kg body weight, specifically from about 0.03 to 2.5 mg/kg body weight. The daily dosage for larger mammals, such as humans, may be from about 0.5 mg to about 2000 mg, or more specifically from 0.5 mg to 1000 mg, administered in a convenient form, e.g., in divided doses up to four times daily or In extended release form. Suitable unit dosage forms for oral administration contain from about 1 to 50 mg of active ingredient.

The compounds of the invention may be administered in the form of pharmaceutical compositions by any conventional route; for example enterally, for example orally, for example in the form of tablets or capsules, parenterally, for example in the form of injectable solutions or suspensions; or administered topically, for example in lotions, gels, ointments or creams, or in nasal or suppository form.

The pharmaceutical composition containing the compound of the present invention in free form or pharmaceutically acceptable salt form and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or freeze-dried in a conventional manner. to manufacture. For example, a pharmaceutical composition comprising a compound of the present invention in combination with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing with the pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active agent.

In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an aqueous isotonic solution. In the case of lyophilized compositions containing the active ingredient alone or in admixture with a carrier such as mannitol, a dispersion or suspension can be prepared before use. The pharmaceutical compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts to adjust the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain a thickening agent including, but not limited to, sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or a solubilizing agent such as Tween 80 (polyoxyethylene (20) Sorbitan monooleate).

Suspensions in oil may contain as oily ingredients vegetable oils, synthetic or semi-synthetic oils commonly used for injectable purposes. Examples include liquid fatty acids containing as the acid component a long chain fatty acid having 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. ester. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated Acids such as oleic acid, elaidic acid, erucic acid, brazilic acid and linoleic acid and, if desired, antioxidants such as vitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene . The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as a mono-, di- or trivalent alcohol. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, ethylene glycol and glycerin.

Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M2375, (polyoxyethylene glycerol), LABRAFIL® M1944 CS (prepared by alcoholysis of almond oil Unsaturated polyethylene glycol glyceride, containing glyceryl ester and polyethylene glycol ester), LABRASOL ^TM (saturated polyethylene glycol glyceride prepared by alcoholysis of TCM, containing glycerol ester and polyethylene glycol ester; both can be obtained from GaKefosse, France), and/or MIGLYOL® 812 (saturated fatty acid triglyceride with chain length from C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil , soybean oil or peanut oil.

Pharmaceutical compositions for oral administration may be prepared, for example, by mixing the active ingredients with one or more solid carriers, granulating the resulting mixture, if necessary, and processing the mixture or granules by adding additional excipients, In the form of tablets or cores.

Suitable carriers include, but are not limited to, fillers such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates such as tricalcium phosphate or dicalcium phosphate, and binders such as starches, Examples include corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl Methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if necessary, a disintegrant such as the above-mentioned starch, carboxymethylstarch, cross-linked polyvinylpyrrolidone, alginic acid or its Salt, such as sodium alginate. Additional excipients include flow conditioners and lubricants, such as silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof .

The tablet cores may be provided with a suitable, optionally enteric coating, by using, inter alia, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or dissolved in Coating solutions of suitable organic solvents or solvent mixtures or, for enteric coatings, solutions of suitable cellulose preparations, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate solutions. Dyestuffs or pigments may be added to the tablets or tablet coatings, for example, for labeling purposes or to indicate different doses of the active ingredient.

Pharmaceutical compositions for oral administration may also include hard capsules including gelatin or soft sealed capsules containing gelatin and a plasticizer such as glycerin or sorbitol. Hard capsules may contain the active ingredient in the form of granules, for example mixed with fillers such as cornstarch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredients can be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oils or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and Detergents, such as fatty acid esters of polyoxyethylene sorbitol, may also be added.

Pharmaceutical compositions suitable for rectal administration, such as suppositories, contain an active ingredient in combination with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration may contain the active ingredient in water-soluble form, such as a water-soluble salt or an aqueous injectable suspension containing viscosity-increasing substances, such as sodium carboxymethylcellulose, aqueous solutions of sorbitol and/or or dextran, and, if necessary, stabilizers. The active ingredient, optionally with excipients, can also be in a lyophilized form and a solution can be prepared by adding a suitable solvent before parenteral administration. Solutions used, for example, for parenteral administration, can also be used as infusion solutions. Injectable preparations are usually prepared under sterile conditions, filled into, for example, ampoules or vials, and sealed containers.

The present invention also provides pharmaceutical combinations, such as a kit, comprising a) a compound disclosed in the present invention, which may be in free form or a pharmaceutically acceptable salt form, and b) at least one auxiliary agent. The kit may contain instructions for its use.

combination therapy

The compounds or pharmaceutically acceptable salts described in this patent can be used alone or in combination with other therapeutic agents.

For example, the use of an adjuvant can enhance the therapeutic effect of a compound of the invention (for example, the therapeutic benefit of an adjuvant drug alone is minimal, but when combined with another drug, the therapeutic benefit of the individual can be enhanced), Alternatively, for example, a compound of the present invention may be combined with another therapeutic agent that is also efficacious to enhance the therapeutic benefit in an individual. For example, when treating gout, the clinical benefit may be enhanced when using a compound of the present invention in combination with another drug used to treat gout. Alternatively, for example, if an adverse effect of using a compound of the invention is nausea, an anti-nausea drug may be used in combination. Alternatively, combined therapies include, but are not limited to, physical therapy, psychotherapy, Radiation therapy, compression therapy in diseased areas, rest, dietary modification, etc. Regardless of the disease, disorder or condition, there should be an additive or synergistic effect between two therapies to benefit an individual's treatment.

In the case where the patented compound is used in combination with other therapeutic agents, the route of administration of the pharmaceutical composition of the patented compound may be the same as that of other drugs, or the route of administration may be different due to different physical and chemical properties. For example, oral administration of a patented compound may produce and maintain favorable blood levels, whereas another therapeutic agent may require intravenous administration. Therefore, the patented compound and another therapeutic agent can be administered simultaneously, sequentially or separately.

There are many methods for synthesizing the compound of formula (I) or its pharmaceutically acceptable salt, and the representative method is listed in this example. However, it should be noted that the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized through other synthesis schemes.

In a compound of formula (I), the connection between atoms and other atoms may lead to the existence of special stereoisomers (such as chiral centers). The synthesis of compounds of formula (I) or pharmaceutically acceptable salts thereof may give rise to mixtures of different isomers (enantiomers, diastereomers). Unless a specific stereoconfiguration is specified, the compounds listed include the different stereoisomers that may exist.

Compounds of formula (I) may also be prepared as pharmaceutically acceptable acid addition salts, for example, by reacting the free form of the compound of the invention with a pharmaceutically acceptable inorganic or organic acid. or The method is to react a compound of formula (I) in the form of a free acid with a pharmaceutically acceptable inorganic or organic alkaloid to prepare a pharmaceutically acceptable alkaloid salt. Inorganic and organic acids and salts suitable for the preparation of pharmaceutically acceptable salts of compounds of formula (I) are described in the definitions section of this application. In addition, salt forms of the compounds of formula (I) can also be prepared by using salts of starting materials or intermediates.

The free acid or free alkaloid of the compound of formula (I) can be prepared from its corresponding alkaloid or acid addition salt. The acid addition salt form of the compounds of formula (I) can be converted into the corresponding free alkaloids, for example by treatment with a suitable alkaloid (eg ammonium hydroxide solution, sodium hydroxide, etc.). The alfadition salt form of the compounds of formula (I) can be converted into the corresponding free acid, for example by treatment with a suitable acid (eg hydrochloric acid, etc.).

An N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known in the art. For example, the N-oxide can be prepared by reacting the non-oxidized form of the compound of formula (I) with an oxidizing agent (such as trifluoroperoxyacetic acid, permaleic acid, peroxybenzoic acid) at 0 to 80°C. , peracetic acid and meta-chloroperoxybenzoic acid, etc.) are obtained by reacting in inert organic solvents (such as halogenated hydrocarbons such as dichloromethane). Alternatively, the N-oxides of the compounds of formula (I) can also be prepared from the N-oxides of the starting materials.

The non-oxidized form of the compound of formula (I) can be obtained by combining its N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride and phosphorus tribromide, etc.) It is prepared by reacting in corresponding inert organic solvents (such as acetonitrile, ethanol and dioxane aqueous solution, etc.) at 0~80°C.

Protected derivatives of compounds of formula (I) can be prepared by methods well known to those in the art. For a detailed technical description of the addition and removal of protecting groups see: T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

The notations and common sense used in these methods, routes and examples are consistent with current scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise stated, standard one-letter or three-letter abbreviations generally refer to L-form amino acid residues. Unless otherwise stated, all starting materials used were purchased from commercial suppliers and used without further purification. For example, the following abbreviations are used in the examples and throughout the specification: g (gram), mg (milligram), L (liter), mL (millilitre), μL (microliter), psi (pounds per square inch), M ( mol), mM (millimol), iv (intravenous injection), Hz (hertz), MHz (megahertz), mol (mole), mmol (millimol), RT (ambient temperature), min (minutes), h (hours) ), mp (melting point), TLC (thin layer chromatography), Rt (retention time), RP (reverse phase), MeOH (methanol), i-PrOH (isopropyl alcohol), TEA (triethylamine), TFA ( Trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethylstyrene), EtOAc (ethyl acetate), DME (1,2-dimethoxyethane), DCM ( Dichloromethane), DCE (dichloroethane), DMF ( N , N -dimethylformamide), DMPU ( N , N' -dimethylpropenyl urea), CDI (1,1-carbonyl dimethylformamide) Imidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et ₂ O (diethyl ether), EDCI (1 -(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride), BOC (tert-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide) imine), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMSE (2-(trimethylsilyl)ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilica) base), TBS (tert-butyldimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (tert-butyl) , HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolidinyl) hypophosphonium chloride), TBAF (tetra-n-butylammonium fluoride), mCPBA (m-chloroperoxybenzene formic acid).

Ether or Et ₂ O both refers to diethyl ether; brine refers to saturated NaCl aqueous solution. Unless otherwise stated, all temperatures are in degrees Celsius and all reactions are carried out at room temperature in an inert atmosphere.

¹ H NMR spectra were recorded using a Varian Mercury Plus 400 nuclear magnetic resonance spectrometer. Chemical shifts are expressed in ppm. Coupling constants are expressed in Hertz (Hz). The apparent diversity is described by segmentation modes and is designated as s (single peak), d (double peak), t (triplet), q (quartet), m (multiple peak) and br (broad peak).

Low-resolution mass spectrometry (MS) and compound purity data were obtained from a Shimadzu LC/MS single quadrupole system equipped with an electrospray ionization detector (ESI), UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). . Thin layer chromatography uses 0.25mm Xupo chemical silica plate (60F-254), 5% phosphomolybdic acid ethanol solution, ninhydrin or p-methoxybenzaldehyde solution and observes under UV lamp. Flash column chromatography used silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.).

Synthesis scheme

Compounds of Formula I or pharmaceutically acceptable salts thereof may be synthesized by various methods, some exemplary methods are provided below and in the Examples. Other synthetic methods can be readily proposed by those skilled in the art based on the information disclosed herein.

In the reactions described below, it may be necessary to protect reactive groups from participating in other undesirable reactions: groups such as hydroxyl, amino, imino, sulfhydryl-containing groups group or carboxyl group, these groups are contained in the final product. Commonly used protecting groups can be found in T.W.Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

Synthetic schemes for all compounds of the present invention are illustrated by the following schemes and examples. The starting materials used are derived from commercial products or can be prepared according to existing processes or the methods illustrated here.

The intermediates listed in the following synthesis scheme were either obtained according to literature or synthesized according to existing similar synthesis methods.

A synthetic method of the compound of formula I disclosed in the present invention is shown in Synthesis Scheme 1. Starting from intermediate II that is commercially available or known in the literature, intermediate formula IV is prepared by coupling intermediate formula II with formula III. The amine V further replaces the leaving group in the intermediate formula IV to obtain the compound of formula I.

As an illustration of the preparation method of the compound of formula I, one synthesis method of the compound of formula Ia is shown in Scheme 2. Starting from the commercially available 5-bromo-7-azindole IIa-A, IIa-C can be obtained by sequentially replacing bromine with sodium methoxide and protecting NH with TIPSCl. IIa-D was prepared by introducing fluorine into IIa-C via directed ortho-metallation (DoM). After the departure of the TIPS leaving group in IIa-D, bromination reaction occurs with NBS to obtain bromide IIa. Then combined with intermediate III, IVa is prepared under n-butyllithium (n-BuLi) conditions. The reaction of amine V with aryl fluoride IVa under the action of anhydride (such as N,N -diisopropylethylamine (DIPEA)) gives compounds of formula Ia.

As an example of another preparation method for the compound of formula I, a synthetic route for the compound of formula Ib is shown in Synthesis Scheme 3. The NH in the azoindole compound IIb-A (commercially available) is protected, and then fluorinated with N -fluorobenzenesulfonamide to obtain the fluorine compound IIb-C. Difluoro compounds IIb-D can be prepared by the DoM method as shown in Synthetic Scheme 2 via IIb-C generation. The leaving group TIPS in IIb-D then undergoes bromination reaction with NBS to convert IIb-D into bromide IIb-E. IIb-E is converted into Ib through the reaction as described in Scheme 3.

In some cases, in order to promote the reaction or avoid the production of unnecessary reaction products, the order of the above synthesis scheme can be adjusted according to the situation. In order that the present invention may be more fully understood, the following examples are provided. These examples are only examples and should not be construed as limitations of the invention.

Intermediate A

Methyl 2-chloro-4-phenoxybenzoate (A)

Methyl 2-chloro-4-phenoxy benzoate ( A ) was prepared according to patent US9630968, 2017, B1 .

Intermediate B

2-Chloro-6-fluoro-4-phenoxybenzaldehyde ( B )

Methyl 2-chloro-6-fluoro-4-phenoxybenzoate ( B-1 )

Under _N protection, commercially available methyl 4-bromo-2-chloro-6-fluorobenzoate (1.04g, 3.89mmol), phenol (434mg, 4.67mmol), Pd(OAc) ₂ (90.0mg, 0.401 mmol), a mixture of 2-(di-tert-butylphosphine)biphenyl (1.7 mg, 0.0080 mmol) and K ₃ PO ₄ (1.7 g, 8.0 mmol) in toluene (30 mL) was stirred at 90°C overnight. The mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography and eluted with PE to obtain the title compound methyl 2-chloro-6-fluoro-4-phenoxy benzoate ( B-1 ). MS-ESI (m/z): 281 [M+1] ⁺ .

(2-Chloro-6-fluoro-4-phenoxyphenyl)methanol ( B-2 )

To a solution of methyl 2-chloro-6-fluoro-4-phenoxybenzoate ( B-1 ) (50 mg, 0.18 mmol) in THF/EtOH (1 mL/0.5 mL) under an ice-water bath, NaBH was added ₄ (20 mg, 0.53 mmol) and LiCl (22 mg, 0.53 mmol). The reaction solution was stirred at room temperature for 2 h, poured into ice water, extracted with ethyl acetate, washed with water and saturated brine, dried over Na ₂ SO ₄ , and concentrated to obtain (2-chloro-6-fluoro-4-phenoxy The crude product of methanol ( B-2 ) was directly used in the next reaction without further purification. MS-ESI(m/z): 253[M+1] ⁺ .

2-Chloro-6-fluoro-4-phenoxybenzaldehyde ( B )

Under nitrogen protection, (2-chloro-6-fluoro-4-phenoxyphenyl)methanol ( B-2 ) (780mg, 3.08mmol) and MnO ₂ (2.0g, 23mmol) were suspended in toluene (15mL). Stir the turbid liquid at 85°C overnight. The mixture was cooled to room temperature and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (50:1) to obtain the title compound 2-chloro-6-fluoro-4-phenoxybenzaldehyde ( B ). MS-ESI(m/z): 251[M+1] ⁺ .

Example 1

(2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine- 3-yl)methanone (1)

3-Bromo-4-chloro-1H-pyrrolo[2,3-b1pyridine ( 1a )

To a commercial solution of 4-chloro-1 H -pyrrolo[2,3- b ]pyridine (1.525 g, 10.00 mmol) in DMF (15 mL) at room temperature was added NBS (1.87 g, 10.50 mmol). The mixture was stirred at room temperature for 1.5 h. The reaction solution was poured into water (50 mL), and the precipitated solid was collected by filtration, washed with water, and dried in air to obtain 3-bromo-4-chloro- 1H -pyrrolo[2,3-b]pyridine ( 1a ) . MS-ESI(m/z): 231/233/235(1:1.2:0.3)[M+1] ⁺ .

(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone ( 1b )

To a solution of 3-bromo-4-chloro- 1H -pyrrolo[2,3- b ]pyridine ( 1a ) (244mg, 1.06mmol) in THF (7mL) at -78°C, n-butyllithium was added dropwise (2.5M hexane solution, 0.89mL, 2.2mmol). The mixture was stirred at this temperature for 1 h, then a solution of methyl 2-chloro-4-phenoxybenzoate ( A ) in THF (2 mL) was added dropwise. The mixture was stirred at -78°C for one hour. At this temperature, IN HCl (3 mL) was added slowly. The mixture was then warmed to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2×). The extract was washed with brine and dried _{over Na2SO4} . The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20-70% EtOAc/n-hexane) to obtain (4-chloro- 1H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro -4-phenoxyphenyl)methanone ( 1b ). MS-ESI(m/z): 383[M+1] ⁺ .

((1r,4r)-4-Aminocyclohexyl)methanol trifluoroacetate ( 1c )

To a solution of commercially available tert-butyl (( 1r,4r )-4-(hydroxymethyl)cyclohexyl)carbamate (1.00 g, 4.36 mmol) in DCE (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness to obtain (( 1r,4r )-4-aminocyclohexyl)methanol trifluoroacetate ( 1c ). MS-ESI(m/z): 130[M+1] ⁺ .

(2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine- 3-yl)methanone ( 1 )

To ((1 r ,4 r )-4-aminocyclohexyl)methanol trifluoroacetate ( 1c ) (56.0 mg, 0.23 mmol), and (4-chloro-1 H -pyrrolo[2,3-b] Pd ₂ (dba) ₃ ( 10.5 mg, 0.0115 mmol), xantphos (13.3 mg, 0.023 mmol) and Cs ₂ CO ₃ (150 mg, 0.46 mmol). The mixture was stirred at 110°C under nitrogen protection for 54 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate (2x). The extract was dried over Na ₂ SO ₄ and concentrated to obtain crude product. Purify by silica gel column chromatography (eluent: 5% methanol/DCM) to obtain (2-chloro-4-phenoxyphenyl) (4-(((1 r ,4 r )-4-(hydroxymethyl) )cyclohexyl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone ( 1 ). MS-ESI(m/z): 476[M+1] ⁺ .

Example 2

(2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-1H-pyrrolo [2,3-b]pyridin-3-yl)methanone ( 2 )

((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride ( 2a )

The title compound (( 2S , 5R )-5-aminotetrahydro- 2H -pyran-2-yl)methanol hydrochloride ( 2a ) was prepared according to patent US2018/051235 .

(2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-1H-pyrrolo [2,3-b]pyridin-3-yl)methanone ( 2 )

To ((2 S ,5 R )-5-aminotetrahydro-2 H -pyran-2-yl)methanol hydrochloride ( 2a ) (122 mg, 0.50 mmol), and (4-chloro-1 H -pyrrole To a solution of [2,3- b ]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone ( 1b ) (89.6mg, 0.234mmol) in n-butanol (2mL) was added DIPEA (130mg, 1.0mmol). The mixture was stirred at 125°C overnight under nitrogen protection. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3x). The extract was washed with brine, dried over Na ₂ SO ₄ and concentrated to obtain crude product. Purify by silica gel column chromatography (eluent: DCM/MeOH=20:1) to obtain the title compound (2-chloro-4-phenoxyphenyl) (4-(((3 R ,6 S )-6- (hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone ( 2 ). MS-ESI(m/z): 478[M+1] ⁺ .

Example 3

(2-Chloro-6-fluoro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)- 1H-pyrrolo[2,3-b]pyridin-3-yl)methanone ( 3 )

(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol ( 3a )

According to the synthesis method in Example 1b , methyl 2-chloro-4-phenoxybenzoate ( A ) is replaced by 2-chloro-6-fluoro-4-phenoxybenzaldehyde ( B ) to prepare Title compound (4-chloro-1 H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol ( 3a ). MS-ESI(m/z): 403[M+1] ⁺ .

(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanone ( 3b )

To (4-chloro-1 H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol ( 3a ) at room temperature (30 mg, 0.07 mmol) in DMSO solution, add IBX (40 mg, 0.14 mmol). The reaction solution was stirred at room temperature for 1 hour, poured into ice water, and extracted with ethyl acetate (3x). The extraction phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purify by silica gel column chromatography (eluent: PE/EA=3:1) to obtain the title compound (4-chloro- 1H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro- 6-Fluoro-4-phenoxyphenyl)methanone ( 3b ). MS-ESI(m/z): 401[M+1] ⁺ .

(2-Chloro-6-fluoro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)- 1H-pyrrolo[2,3-b]pyridin-3-yl)methanone ( 3 )

According to the synthesis method in Example 2 , (4-chloro- 1H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone ( 1b ) was replaced with (4-chloro-1 H -pyrrolo[2,3- b ]pyridin-3-yl) (2-chloro-6-fluoro-4-phenoxyphenyl)methanone ( 3b ) to prepare Title compound (2-chloro-6-fluoro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone ( 3 ). MS-ESI(m/z): 496[M+1] ⁺ .

Example 4-225 listed in Table 1 is basically the same method as Example 1-3, and the starting materials used are commercially available or prepared according to literature methods. Table 1 gives the name and structure of Example 4-225.

Kinase test

The kinase activity of BTK(C481S) was measured at Reaction Biology Corporation. Prepare BTK(C481S) in fresh reaction buffer (20mM Hepes (pH 7.5), 10mM MgCl ₂ , 1mM EGTA, 0.02% Brij35, 0.02mg/ml BSA, 0.1mM Na ₃ VO ₄ , 2mM DTT, 1% DMSO) Reaction substrate pEY (poly[Glu:Tyr](4:1)) (Sigma, Cat.# P7244-250MG). BTK(C481S) (SignalChem, Cat.# B10-12CH) was added to the substrate solution and mixed gently. The final concentrations of BTK(C481S) and substrate in the reaction system were 6nM and 0.2mg/ml respectively. Test compounds will be diluted 3-fold in a 10 concentration/response pattern starting at 1 μM.

Test compounds dissolved in 100% DMSO were added to the kinase reaction via an ultrasonic fluid handling system (Echo550; nanoliter range) and incubated at room temperature for 20 minutes. Add 10 μM of [ ³³ P]-ATP (ATP: Sigma, Cat.# A7699; [ ³³ P]-ATP: Hartmann Analytic, Cat.# SCF-301-12) to the reaction solution to initiate the reaction, and incubate at room temperature. 120 minutes. Fluorescence intensity is detected using specific affinity analysis methods. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio with the control group (DMSO), and the IC ₅₀ value of the compound was obtained through GraphPad Prism software.

Selected compounds are assayed according to the biological methods described herein. The results are shown in Table 2:

cell proliferation assay

By measuring the inhibitory effect of compounds on DOHH2 (DSMZ catalog #: ACC47) cell proliferation, we studied whether the compounds can inhibit the activity of BTK in cells. In the assay, the compound's inhibitory activity against BTK was tested by inhibiting DOHH2 cell proliferation. Digest the cells, seed them in a 96-well plate at a cell concentration of 5000 cells/well, and incubate at 37°C and 5% _CO2 for 4 hours. Compounds of different concentrations (final concentrations 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5nM) were added to 3 parallel wells in a 96-well cell culture plate and incubated for 120h at 37°C and 5% _CO2 . Add MTS to each well at a concentration of 20 μL MTS per 100 μL culture medium. After incubation for 2 hours, 25 μL of 10% SDS was added to each well to terminate the reaction. Measure the absorbance at 490nm and 650nm with a microplate reader. _IC50 was calculated using GraphPad Prism 5.0.

Selected compounds are assayed according to the biological methods described herein. The results are shown in Table 3:

Pharmacokinetic experiments

The purpose of this experiment was to study the pharmacokinetic properties of Example 71 and Example 75 in male Sprague-Dawley (SD) rats (provided by Beijing Vitong Lever Experimental Animal Technology Co., Ltd.).

The animals in the first group were given a single intravenous injection of Example 71 at 1 mg/kg and 1 mg/mL, and the animals in the second group were given a single intragastric administration of the solution of Example 71 at 5 mg/kg and 1 mg/mL respectively. The solvents of these two groups of dosage preparations are 60% Phosal 50 PG (Lipoid, batch number: 368315-3180028/009): 30% polyethylene glycol 400 (Sigma, batch number: MKCH6281): 10% ethanol (Merck, batch number: K48244883634 ). Determination of plasma samples using LC/MS/MS method Concentrations of Example 71. (Liquid phase: Waters UPLC; Mass spectrometry: API4000). The results are shown in Table 4.

The animals in Group 3 were given a single intravenous injection of 2 mg/kg, 2 mg/mL Example 75 solution, and the animals in Group 4 were given a single intravenous injection of 10 mg/kg, 2 mg/mL Example 75 solution. The solvents of the two groups of administration preparations were 10% dimethyl styrene (Sigma, batch number: LPC0S181): 60% polyethylene glycol 400 (Sigma, batch number: MKCH6281): 30% water. The concentration of Example 75 in plasma samples was determined using the LC/MS/MS method. (Liquid phase: Waters UPLC; Mass spectrometry: Triple Quad 6500 plus). The results are shown in Table 4.

Claims (18)

A compound represented by formula (II):

or a pharmaceutically acceptable salt thereof, wherein Q is selected from

and

, is unsubstituted or substituted by at least one substituent independently selected from R ^X ; L is -O-; Substructure (IV) of formula (II)

Selected from

and

^, _where ^{R _} _{_} ^{_ _} _{_ -10} alkyl; R ¹ is selected from C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from R ^X1 ; R ² is selected from hydrogen, halogen, -OR ^A2 , and CN; R ³ is hydrogen; R ⁴ is hydrogen; R ⁵ is selected from phenyl and pyridyl, wherein the phenyl and the pyridyl are respectively unsubstituted or at least one substituent independently selected from ^R _Substituted , wherein ^{the substituent R Substituted from} _a ^{substituent of R _ _} _{_} ^{_ _ _} _{_} (O)R ^b1 , -(CR ^c1 R ^e1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t OC( O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , and -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , where each Each t is 0, each R ^a1 is hydrogen, each R ^b1 is independently selected from hydrogen, C _1-10 alkyl and C _3-10 cycloalkyl; each R ^X2 is independently selected from deuterium and halogen; each R ^and _{_} ^{_ _} Halogen, CN, and -OR ^a2 ; each R ^a2 is hydrogen; each r is 2. The compound of claim 1 or _a pharmaceutically acceptable salt thereof, wherein the substituent ^R Substituted with a substituent selected from R ^Y. Such as the compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X of Q is a methyl group, and the substituent R ^Y of the methyl group is F or OH. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, and the substituent R ^X1 of the methyl group is selected from OH,

The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein substructure (III) of formula (II)

Selected from

The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein the R ^X' is selected from hydrogen, F, Cl, Br, CN, methyl and methoxy. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the R ^X' is selected from hydrogen, F, Cl and methyl. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a phenyl group, wherein the phenyl group is unsubstituted or substituted by at least one substituent independently selected from ^R replace. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R ^X5 is halogen. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a pyridyl group, wherein the pyridyl group is unsubstituted. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from phenyl,

The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F, Cl, methoxy, ethoxy, CN,

A compound as described in claim 1, selected from:

and pharmaceutically acceptable salts thereof. A compound as described in claim 1, selected from:

, and its pharmaceutically acceptable salts. A compound as described in claim 1, selected from:

, and its pharmaceutically acceptable salts. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-15 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 16 for use in the treatment or improvement of effects on inhibiting BTK. Use in medicine in response to a condition, and wherein the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is optionally combined with a second therapeutic agent. Use of a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of abnormal cell proliferation diseases.