{"paper_id":"569cc8fa-f3dc-47bb-b8f2-d34be516ffa2","body_text":"Protein kinases (PKs) are ubiquitous intracellular and cell surface enzymatic proteins that selectively catalyzes phosphate group’s relocation from ATP, GTP, and other phosphate donors to protein substrates [ 1 ]. The PKs mainly catalyze the relocation of a γ-phosphatase group of ATP to the oxygen atom of the -OH group of threonine, serine, and tyrosine residues in peptides/polypeptides, thereby making a conformational variation from an inactive to an active form [ 1 , 2 ]. They constitute an extensive family of structurally related enzymes that are known to be implicated in almost all the signal transduction activities, frequently with cascades of phosphorylation proceedings taking place within the cell [ 3 ]. The signal transduction involves the reversible phosphorylation of proteins that helps to regulate mature proteins by altering their structure and function [ 4 , 5 ]. To date, nearly 535 human PKs have been identified [ 6 ], wherein more than 478 belong to a superfamily whose catalytic domains are sequentially interrelated. These PKs are additionally categorized into groups, families, and subfamilies established on their biochemical activities. The main two classifications are Serine/threonine PKs and Tyrosine-specific PKs [ 5 ]. The seven significant groups with the description of families, subfamilies, and functions are listed in  Table 1 .\nTKs form a distinct group, which phosphorylates proteins on tyrosine, whereas others phosphorylate serine and threonine residues. In addition to this category, there are atypical kinases, which are not related to any sequence resemblance to characteristic kinases but are well recognized for their enzymatic activity similar to specific kinases. Some kinases are believed to lack the catalytic domain for effective phosphorylation and are called pseudokinases. Still, they are distributed across all kinase families, indicating that an absence of catalysis is not a formal barricade to the evolution of unique or irreplaceable biological functions [ 7 ].\nFamilies and subfamilies of PKs.\nPKs perform a significant function in signal transduction and control of most cellular processes, including cell growth, differentiation, proliferation, angiogenesis, apoptosis, cytoskeletal arrangement, regulation of metabolic reactions, membrane transport, and motility, etc. [ 6 ]. Non-catalytic functions of PKs are also essential and include the allosteric effect, subcellular targeting, the scaffolding of protein complexes, competition for protein interactions, and DNA binding [ 15 ]. Because PKs regulate most fundamental biological processes, any dysregulation, genetic alteration, and abrupt change in kinase function are typically linked with pathological conditions such as cancer, immunologic, neurological, cardiovascular, and metabolic disorders [ 3 , 5 ]. Hence, manipulation of PKs signaling pathway, regulation, and inhibition constitutes important clinical targets for pharmacological intervention and thus for the identification and development of Protein Kinase Inhibitors (PKIs) to manage and treat several chronic diseases [ 4 , 6 , 16 ]. Over the past two decades, approximately 1/5th-1/3rd drug discovery programs worldwide have targeted PKs for the drug development of various illnesses.\nKinase mutation frequency is much less, and thus targeting kinases could be helpful in life-saving therapies especially for cancer. A well-known example is receptor tyrosine kinase ALK where gene fusion between EML4 and ALK occurs only in 5% of NSCLC patients and therefore many patients responded to the kinome therapy effectively. Identification of additional effective kinome targets will therefore represent an Achilles heel in a subset of cancer. The use of bioinformatics tools in predicting the likelihood that a given mutation will alter the function of a kinase will be essential in pinpointing cancer-associated kinases [ 17 ].\nThere are about 175 kinase drugs under clinical trials and newer targets are also under evaluation including AKT, Aurora kinases, CHEK1, and CDK1. However, most of the drugs under investigation are well known for targeting EGFR, VEGFR, PI3K, and mTOR [ 18 ]. Even though CAMK, CK1, or AGC kinases groups are well-known and evidenced as the primary targets for cancer, there are no investigational drugs that target these kinases are enrolled. So far only 8% of the entire kinome has been effectively “drugged” and a quarter of human kinases are vastly understudied [ 19 ]. A wide-ranging scoring system to rank and prioritize clinically relevant kinase targets of different solid tumor cancers from The Cancer Genome Atlas (TCGA) has been developed [ 19 ].\nSuccessful applications and deep insights into the ever-diversifying therapeutic space occupied by kinase targets are also explored. For effective target validation and to avoid complicating off-target mediated response it is essential to achieve the desired selectivity while targeting kinases, though it is still an ongoing challenge. The application of large-scale omics data has been modernized to combine multiple parameters to evaluate the protein’s potential as a drug target or biomarker [ 19 ].\nIn recent years, intricately selective kinase chemical probes have been generated by the exploitation of unique pockets using molecular modeling and bioinformatics, prioritizing the ligand-efficient leads and novel chemotypes and the extensive use of kinome-wide profiling [ 20 ].\nChemical proteomics and broad kinome profiling of compound libraries have been implemented as an efficient method to lead to discovery, analyzing targets, and optimization [ 21 ]. Results revealed that unknown targets for established drugs presented a viewpoint on the \"druggable\" kinome, emphasized non-kinase off-targets, and recommended for potential therapeutic applications. A database of the cellular targets of 243 clinical kinase inhibitors has been made available using kinobead technology [ 21 ].\nThe ongoing research will undoubtedly pave the way for a better understanding of molecular pathways that will further unravel the role of PKs in pathogenesis. As of now, the majority of the USFDA-approved PKIs are Protein Tyrosine Kinase inhibitors (PTKIs) followed by protein-serine/threonine PKIs. Most of these drugs are clinically used to treat solid (breast, lung, colon) and non-solid tumors (leukemia). Some PKIs are also effective in treating non-malignant diseases, including myelofibrosis, rheumatoid arthritis, glaucoma, ulcerative colitis, pulmonary fibrosis, etc. [ 22 , 23 ].\n\nIn 2001, the USFDA approved the marketing of the first clinical PKI, imatinib. Since then, the USFDA has approved about 70 PKIs for clinical use ( Table 2 ) ( Figure 1 ). The data provided in  Table 2  have been obtained from USFDA’s Orange Book website ( https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm?resetfields=1  (accessed on 31 May 2021) using the drug’s name.\n\nThe patent searching was performed using the Sci-finder database (CAS Number search, and the exact structure search of each TKI), USFDA’s Orange Book website (mentioned above), and the Drugbank’s website ( https://go.drugbank.com/  (accessed on 31 May 2021)) using the drug’s name. The patents disclosing the specific TKI, its marketed active pharmaceutical ingredient, and important polymorphs from the innovative company for the first time were identified and included in this review. The patents of each TKI that claim its treatment methods, dosage forms, formulations, drug combinations, particle size, impurity, preparation process, intermediates, etc., have been excluded from this review. The expiry dates of the selected patents were calculated (20 years from the patent application filing date comprising patent term extension, if any). Sometimes, the drug’s patent term is extended up to five years based on the USPTO’s laws. Accordingly, the expiry dates of the selected patients were also verified from the USPTO’s website. It was also observed that some TKIs were disclosed in different patents of the same patent family and had other expiry dates. In such cases, the patent that had a more extended expiry date was selected for this review because the generic launch of the drug is based on the expiry date of the drug’s patent. The legal status of the patents cited herein was obtained from the website of USPTO ( https://portal.uspto.gov/pair/PublicPair  (accessed on 31 May 2021)).\n\nThe proprietary name, approved dosage form, approval date, and marketing status of each marketed PKIs are mentioned in  Table 2 . The patent number, applicant/assignee, expiry date, and legal status of the cited patents of each PKI are provided in  Table 3 . A brief description of the PKIs and their important patents are provided below.\nImatinib mesylate ( Figure 2 ) is a pyridine-pyrimidine based piperazine derivative (MF: C 29 H 31 N 7 O·CH 4 SO 3 ; MW: 589.7; CAS Number: 220127-57-1) [ 24 ].  US5521184A  claims  N -phenyl-2-pyrimidine-amine compounds, including imatinib and its pharmaceutically acceptable salts, as antitumor drugs [ 25 ].  USRE43932E  (Re-issue of US7544799B2) claims the β-crystal form of imatinib mesylate as having favorable thermodynamic stability, flow properties, and low hygroscopicity that makes it a suitable active pharmaceutical ingredient (API) to be used in the tablet/capsule dosage forms [ 26 ].\nGefitinib ( Figure 3 ) is a morpholine based quinazolinamine derivative (MF: C 22 H 24 ClFN 4 O 3 ; MW: 446.9; CAS Number: 184475-35-2) [ 27 ].  US5457105A  unveils quinazoline derivatives and their salts to treat neoplastic disease. This patent claims gefitinib generically [ 28 ].  US5770599A  also covers quinazoline derivatives as anticancer agents. This patent claims gefitinib specifically, along with its pharmaceutically acceptable acid-addition salts [ 29 ].\nErlotinib hydrochloride ( Figure 4 ) is a quinazolinamine derivative (MF: C 22 H 23 N 3 O 4 ·HCl; MW: 429.90; CAS Number: 183319-69-9) [ 30 ].  USRE41065E  (Reissue patent of US5747498) discloses 4-(substituted phenylamino)quinazoline derivatives, which are useful in treating cancers. It also claims erlotinib hydrochloride specifically [ 31 ].  US6900221B1  provides polymorphs of erlotinib hydrochloride and processes for their selective production. It claims homogeneous thermodynamically stable crystalline polymorph of erlotinib hydrochloride (Form B), suitable for making tablet dosage forms [ 32 ].\nSorafenib tosylate ( Figure 5 ) is a urea-pyridine based diaryl ether derivative (MF: C 21 H 16 ClF 3 N 4 O 3 ·C 7 H 8 O 3 S; MW: 637.0; CAS Number: 475207-59-1) [ 33 ].  US7235576B1  provides aryl urea derivatives for treating RAF-mediated diseases like cancer and their pharmaceutical compositions. It claims sorafenib tosylate specifically [ 34 ].  US8877933B2  discloses novel polymorphs of sorafenib tosylate, processes for its synthesis, and compositions comprising it. It claims thermodynamically stable polymorph (Form I) of sorafenib tosylate, which can provide quality dosage form concerning bioavailability and patient safety [ 35 ].\nSunitinib malate ( Figure 6 ) is an indole based pyrrole-3-carboxamide derivative (MF: C 22 H 27 FN 4 O 2 ·C 4 H 6 O 5 ; MW: 532.6; CAS Number: 341031-54-7) [ 36 ].  US7125905B2  covers 3-pyrrole substituted 2-indolinone compounds as PK activity modulators for treating disorders related to abnormal PK activity. It claims sunitinib malate specifically [ 37 ]. The sunitinib malate is also claimed in  US6573293B2  [ 38 ].\nDasatinib monohydrate ( Figure 7 ) is a piperazine-pyrimidine-thiazole based anilide (MF: C 22 H 26 ClN 7 O 2 S·H 2 O; MW: 506.02; CAS Number: 863127-77-9) [ 39 ].  US6596746B1  provides cyclic compounds for use as PKIs to treat cancer. It claims dasatinib specifically [ 40 ].  US7491725B2  claims crystalline monohydrate of dasatinib and process for its preparation [ 41 ].\nLapatinib ditosylate monohydrate ( Figure 8 ) is a furan based quinazolinamine derivative (MF: C 29 H 26 ClFN 4 O 4 S·(C 7 H 8 O 3 S) 2 .H 2 O; MW: 943.5; CAS Number: 388082-78-8) [ 42 ].  US8513262B2  discloses substituted heteroaromatic compounds, their synthesis, compositions, and their use in medicine as PTKIs. It claims lapatinib specifically [ 43 ].  US7157466B2  relates to quinazoline compounds, anhydrate and hydrate ditosylate salts thereof, and the process for their preparation. It claims lapatinib ditosylate monohydrate specifically. The claimed lapatinib ditosylate possesses physical stability and moisture sorption properties superior to di-HCl salt, making it suitable for developing tablet formulations [ 44 ].\nTemsirolimus ( Figure 9 ) is a piperidine-tetrahydropyran based macrolide lactams (MF: C 56 H 87 NO 16 ; MW: 1030.30; CAS Number: 162635-04-3) [ 45 ].  USRE44768E  (Reissue of US5362718) relates to hydroxy esters of rapamycin for treating T-cell leukemia/lymphoma, solid tumors, and hyperproliferative vascular disorders. It claims temsirolimus specifically [ 46 ].\nEverolimus ( Figure 10 ) is a piperidine-tetrahydropyran based macrolide lactam (MF: C 53 H 83 NO 14 ; MW: 958.25; CAS Number: 159351-69-6) [ 47 ].  US5665772A  provides alkylated derivatives of rapamycin as immunosuppressants. It claims everolimus specifically [ 48 ].\nNilotinib hydrochloride monohydrate ( Figure 11 ) is a pyridine-pyrimidine-imidazole-based benzanilide derivative (MF: C 28 H 22 F 3 N 7 O·HCl·H 2 O; MW: 584; CAS Number: 923288-90-8) [ 49 ].  US7169791B2  covers substituted pyrimidinyl aminobenzamides, methods of synthesis, and their compositions to treat neoplastic diseases like leukemia. It claims nilotinib and its salts [ 50 ].  US8163904B2  claims nilotinib hydrochloride monohydrate as having physicochemical properties required to develop a good dosage form [ 51 ].  US8415363B2  claims crystalline form B of nilotinib hydrochloride monohydrate having superior crystallinity and physical stability over other polymorphs [ 52 ].\nPazopanib hydrochloride ( Figure 12 ) is a benzenesulfonamide bearing benzimidazole-pyrimidinyl compound (MF: C 21 H 23 N 7 O 2 S·HCl; MW: 473.99; CAS Number: 635702-64-6) [ 53 ].  US7105530B2  reports pyrimidine derivatives as inhibitors of VEGFR-2 to treat disorders, including cancer, associated with inappropriate angiogenesis. It claims pazopanib and its salts [ 54 ].  US8114885B2  claims pazopanib hydrochloride precisely [ 55 ]. The claimed hydrochloride salt possesses advantageous properties like stability and solubility to develop quality dosage forms.\nVandetanib ( Figure 13 ) is a piperidine based 4-aminoquinazolinamine derivative (MF: C 22 H 24 BrFN 4 O 2 ; MW: 475.36; CAS Number: 443913-73-3) [ 56 ].  USRE42353E  (Reissue of US6414148B1) provides quinazoline derivatives, synthesis, and compositions to treat illness linked with angiogenesis and amplified vascular permeability. It claims vandetanib precisely [ 57 ].\nVemurafenib ( Figure 14 ) is a phenylketone based pyrrolopyridine (MF: C 23 H 18 ClF 2 N 3 O 3 S; MW: 489.9; CAS Number: 918504-65-1) [ 58 ].  US8143271B2  describes pyrrolopyridine based compounds as PTKIs to treat diseases and conditions associated with aberrant activity of PTKs. It claims vemurafenib specifically [ 59 ].\nCrizotinib ( Figure 15 ) is a piperidine based pyrazolylpyridine derivative (MF: C 21 H 22 Cl 2 FN 5 O; MW: 450.34; CAS Number: 877399-52-5) [ 60 ].  US7858643B2  describes aminopyridines and aminopyrazines having PTKI activity, methods of synthesizing and using these compounds as anticancer agents. It claims crizotinib and its salts [ 61 ].  US8217057B2  claims a crystalline form of a free base of crizotinib with improved solubility, stability, and physicochemical properties to develop solid dosage forms, such as capsules [ 62 ].\nRuxolitinib phosphate ( Figure 16 ) is a pyrrolo[2,3- d ]pyrimidine based pyrazole derivative (MF: C 17 H 21 N 6 O 4 P; MW: 404.36; CAS Number: 1092939-17-7) [ 63 ].  US7598257B2  provides pyrrolo[2,3- b ]pyridines as JAK modulators, which are beneficial to treat immune-related disorders, skin diseases, myeloid proliferative ailments, and cancer. It claims ruxolitinib and its salts [ 64 ].  US8722693B2  claims ruxolitinib phosphate, which has improved water solubility, dissolution rate, chemical stability, long shelf life, excipients, and reproducibility compared to the free base [ 65 ].\nAxitinib ( Figure 17 ) is a pyridine based indazolylphenyl thioether (MF: C 22 H 18 N 4 OS; MW: 386.47; CAS Number: 319460-85-0) [ 66 ].  US6534524B1  relates to indazole compounds as PTKIs and their pharmaceutical compositions to treat diseases linked with undesirable angiogenesis and cellular proliferation. It claims axitinib specifically [ 67 ].  US8791140B2  claims crystalline forms of axitinib that have advantages in bioavailability, stability, manufacture ability, and suitability for bulk preparation [ 68 ].\nBosutinib monohydrate ( Figure 18 ) is a piperazine based 3-quinolinecarbonitrile derivative (MF: C 26 H 29 Cl 2 N 5 O 3 ·H 2 O; MW: 548.46; CAS Number: 918639-08-4) [ 69 ].  USRE42376E  (Reissue of US6297258B1) describes substituted 3-cyano quinoline compounds as PTKIs to treat diseases resulting from deregulation of PTKs, for example, cancer and polycystic kidney disease. It claims bosutinib [ 70 ].  US7767678B2  claims non-hygroscopic and stable crystalline bosutinib monohydrate (Form I) having good solubility that can be used to prepare different solid dosage forms [ 71 ].\nRegorafenib monohydrate ( Figure 19 ) is pyridinylphenyl urea derivative (MF: C 21 H 15 ClF 4 N 4 O 3 ·H 2 O; MW: 500.83; CAS Number: 1019206-88-2) [ 72 ].  US8637553B2  discloses omega-carboxyaryl diphenyl urea derivatives as potent inhibitors of PDGFR, VEGFR, RAF, and p38 kinase to treat cancer, inflammatory diseases, and osteoporosis. It claims regorafenib and its salts [ 73 ].  US9957232B2  claims regorafenib monohydrate with high stability and good physicochemical features to manufacture pharmaceutical compositions [ 74 ].\nTofacitinib citrate ( Figure 20 ) is an pyrrolo[2,3- d ]pyrimidine based piperidine derivative (MF: C 16 H 20 N 6 O·C 6 H 8 O 7 ; MW: 504.5; CAS Number: 540737-29-9) [ 75 ].  USRE41783E  (Reissue of US6627754B2) provides pyrrolo[2,3- d ]pyrimidines as JAK3 inhibitors to treat rheumatoid arthritis, psoriasis, cancer, and leukemia. It claims tofacitinib and its salt [ 76 ].  US6965027B2  claims a crystalline form of tofacitinib mono citrate salt with solid-state properties (solubility, stability, compressibility, etc.), which are acceptable to support tablet development [ 77 ].\nCabozantinib S-malate ( Figure 21 ) is a quinolinylphenyl ether derivative (MF: C 28 H 24 FN 3 O 5 ·C 4 H 6 O 5 ; MW: 635.6; CAS Number: 1140909-48-3) [ 78 ].  US7579473B2  relates to quinazolines and quinolines as TKIs, and their pharmaceutical compositions to treat psoriasis, multiple sclerosis, and rheumatoid arthritis. It claims cabozantinib and its salts [ 79 ].  US8877776B2  claims cabozantinib (L)-malate salt having desirable solubility and chemical/physical stability to develop a tablet/capsule dosage forms for intended use [ 80 ].\nPonatinib hydrochloride ( Figure 22 ) is animidazo[1,2- b ]pyridazine based piperazine derivative (MF: C 29 H 28 ClF 3 N 6 O; MW: 569.02; CAS Number: 1114544-31-8) [ 81 ].  US8114874B2  describes imidazo[1,2- b ]pyridazines as PTKIs and their pharmaceutical compositions to treat cancer and other diseases mediated by PTKs. It claims ponatinib hydrochloride specifically [ 82 ].  US9493470B2  claims stable crystalline form A of ponatinib hydrochloride that is advantageous for the commercial preparation of solid dosage forms because of its physicochemical stability compared to amorphous ponatinib hydrochloride [ 83 ].\nTrametinib dimethyl sulfoxide ( Figure 23 ) is a pyridopyrimidine derivative (MF: C 26 H 23 FIN 5 O 4 .C 2 H 6 OS; MW: 693.53; CAS Number: 1187431-43-1) [ 84 ].  US7378423B2  unveils pyrimidine compounds, their salts, synthetic procedures, and compositions to treat ailments caused by unwanted cell proliferation, for example, cancer. It claims trametinib dimethyl sulfoxide specifically [ 85 ].\nDabrafenib mesylate ( Figure 24 ) is a pyrimidine-thiazole based diphenyl sulfonamide derivative (MF: C 23 H 20 F 3 N 5 O 2 S 2 .CH 4 O 3 S; MW: 615.68; CAS Number: 1195768-06-9) [ 86 ].  US7994185B2  provides benzene sulfonamide thiazole and oxazole compounds, their pharmaceutical compositions, processes for their preparation, and methods of using these compounds and compositions for treating cancer and melanoma. It claims dabrafenib mesylate specifically [ 87 ].\nAfatinib dimaleate ( Figure 25 ) is a tetrahydrofuran based quinazolinamine derivative (MF: C 32 H 33 ClFN 5 O 11 ; MW: 718.1; CAS Number: 850140-73-7) [ 88 ].  USRE43431E  (Reissue of US7019012B2) unveils quinazoline derivatives and their physiologically acceptable salts possessing an inhibitory effect on signal transduction mediated by PTKs to treat tumoral diseases, diseases of the lungs, and respiratory tract. It claims afatinib dimaleate precisely [ 89 ].  US8426586B2  claims crystalline afatinib dimaleate, synthesis, and its compositions. The claimed crystalline form is stable and has advantageous properties to develop quality dosage forms [ 90 ].\nIbrutinib ( Figure 26 ) is a piperidine based pyrazolo[3,4- d ]pyrimidine (MF: C 25 H 24 N 6 O 2 ; MW: 440.50; CAS Number: 936563-96-1) [ 91 ].  US8735403B2  describes pyrazolo[3,4- d ]pyrimidine based inhibitors of BTK, their synthesis, and compositions to treat diseases, wherein inhibition of BTK delivers therapeutic advantage to the diseased person. It claims ibrutinib specifically [ 92 ].  US9296753B2  claims stable, water-soluble, and non-hygroscopic crystalline ibrutinib that can be used to manufacture quality dosage forms [ 93 ].\nCeritinib ( Figure 27 ) is a pyrimidine based phenylpiperidine derivative (MF: C 28 H 36 N 5 O 3 ClS; MW: 558.14; CAS Number: 1032900-25-6) [ 94 ].  US8039479B2  reveals pyrimidine and pyridine derivatives and their pharmaceutical compositions to treat a condition that responds to inhibition of ALK, FAK, ZAP-70, IGF-1R, or a combination thereof. It claims ceritinib specifically [ 95 ].  US9309229B2  claims a pure and stable crystalline form of ceritinib with desirable physicochemical properties to provide good dosage forms [ 96 ].\nIdelalisib ( Figure 28 ) is a purine based quinazolinone derivative (MF: C 22 H 18 FN 7 O; MW: 415.42; CAS Number: 870281-82-6) [ 97 ].  USRE44638E  (Reissue of US7932260B2) reports substituted quinazolinone compounds as PI3K δ  inhibitors to treat diseases like bone-resorption disorders, hematopoietic cancers, lymphomas, multiple myelomas, and leukemia. It claims idelalisib and its salts [ 98 ].  US9469643B2  claims a water-soluble bioavailable and stable polymorph of idelalisib (Form II) that can be used to provide quality dosage forms [ 99 ].\nNintedanib esylate ( Figure 29 ) is a piperazine based indole carboxylic acid derivative (MF: C 31 H 33 N 5 O 4 .C 2 H 6 O 3 S; MW: 649.76; CAS Number: 656247-18-6) [ 100 ].  US6762180B1  states indolinone derivatives as PTKIs, synthesis, and compositions to treat proliferative sicknesses. It claims nintedanib and its salts [ 101 ].  US7119093B2  claims a stable nintedanib esylate salt specifically characterized by good crystallinity and low amorphization during grinding and compression. This salt is claimed to have good physicochemical characteristics to support quality dosage forms [ 102 ].\nPalbociclib ( Figure 30 ) is a pyrido[2,3- d ]pyrimidine based pyridinylpiperazine derivative (MF: C 24 H 29 N 7 O 2 ; MW: 447.54; CAS: 571190-30-2) [ 103 ].  USRE47739E  (Reissue of US7208489B2) delivers substituted 2-amino pyridines as potent inhibitors of CDK 4, useful for treating inflammation and proliferative cell diseases such as cancer and restenosis. It claims palbociclib and its salts [ 104 ].  US10723730B2  claims a stable crystalline free base of palbociclib with larger primary particle size, reduced specific surface area, lower surface energy measurements, and physicochemical properties to formulate a good dosage form [ 105 ].\nLenvatinib mesylate ( Figure 31 ) is a quinoline carboxamide derivative (MF: C 21 H 19 ClN 4 O 4 .CH 4 O 3 S; MW: 522.96; CAS Number: 857890-39-2) [ 106 ].  US7253286B2  reports nitrogen-containing aromatic derivatives and salts or hydrates thereof to treat various diseases associated with abnormal angiogenesis. It claims lenvatinib and its pharmacologically active salts [ 107 ].  US7612208B2  claims a crystalline form of lenvatinib mesylate with improved features (physical/pharmacokinetics) compared to the free-form [ 108 ].\nCobimetinib fumarate ( Figure 32 ) is a piperidine-azetidine based anthranilamide derivative (MF: C 46 H 46 F 6 I 2 N 6 O 8  (2C 21 H 21 F 3 IN 3 O 2 .C 4 H 4 O 4 ); MW: 1178.71; CAS Number: 1369665-02-0) [ 109 ].  US7803839B2  provides azetidin-1-yl(2-(2-fluorophenylamino)cyclic)methanone derivatives as inhibitors of MEK that are useful in cancer treatment. It claims cobimetinib and its salts [ 110 ].  US10590102B2  claims a thermodynamically stable and non-hygroscopic crystalline fumarate salt (Form A) of cobimetinib with suitable properties for use in a pharmaceutical composition [ 111 ].\nOsimertinib mesylate ( Figure 33 ) is a pyrimidine based indole derivative (MF: C 28 H 33 N 7 O 2 .CH 4 O 3 S; MW: 596; CAS Number: 1421373-66-1) [ 112 ].  US8946235B2  states 2-(2,4,5-substituted-anilino)pyrimidines, useful in treating a disease mediated by EGFR, for example, cancer. It claims osimertinib mesylate specifically [ 113 ].\nAlectinib hydrochloride ( Figure 34 ) is a morpholine-piperidine based carbazole derivatives (MF: C 30 H 34 N 4 O 2 ·HCl; MW: 519.08; CAS Number: 1256589-74-8) [ 114 ].  US9126931B2  relates to tetracyclic compounds as ALK inhibitors for treating a disease accompanied by an abnormality in ALK, for example, cancer, depression, and cognitive function disorder. It claims alectinib and its salts [ 115 ].\nRibociclib succinate ( Figure 35 ) is a pyridine-piperazine based pyrrolo[2,3- d ]pyrimidine derivative (MF: C 23 H 30 N 8 O·C 4 H 6 O 4 ; MW: 552.64; CAS Number: 1374639-75-4) [ 116 ].  US8415355B2  discloses pyrrolopyrimidine compounds, the process for their preparation, and their pharmaceutical compositions to treat a disease linked with CDK 4 inhibition. It claims ribociclib and its salts [ 117 ].  US9193732B2  claims succinate salt of ribociclib that has good stability, non-hygroscopicity, and good solubility. These features make this salt a suitable salt to develop the desired formulation [ 118 ].\nBrigatinib ( Figure 36 ) is a piperazine-piperidine based pyrimidine derivative (MF: C 29 H 39 ClN 7 O 2 P; MW: 584.10; CAS Number: 1197953-54-0) [ 119 ].  US9012462B2  narrates phosphorous compounds as PTKIs and their use in treating cancers. It claims brigatinib and its salts [ 120 ].  US10385078B2  claims a stable and non-hygroscopic anhydrous crystalline form A of brigatinib suitable for pharmaceutical formulation development [ 121 ].\nMidostaurin ( Figure 37 ) is an indolocarbazole derivative (MF: C 35 H 30 N 4 O 4 ; MW: 570.65; CAS Number: 120685-11-2) [ 122 ].  US5093330A  relates to staurosporine derivatives, their salts, synthesis, and compositions encompassing them to treat cancer and inflammation. It discloses midostaurin [ 123 ].  US7973031B2  claims a method for treating AML using a dosage form (a microemulsion, soft gel, or solid dispersion) of midostaurin, wherein the AML is characterized by deregulated FLT3 receptor tyrosine kinase activity [ 124 ].\nNeratinib maleate ( Figure 38 ) is a pyridine based 4-aminoquinoline derivative (MF: C 30 H 29 ClN 6 O 3 ·C 4 H 4 O 4 ; MW: 673.11; CAS Number: 915942-22-2) [ 125 ].  US7399865B2  reports substituted 3-cyanoquinoline compounds and their salts as inhibitors of HER-2 and EGFR to treat cancer. It claims neratinib and its salts [ 126 ].\nCopanlisib dihydrochloride ( Figure 39 ) is a morpholine-pyrimidine based 2,3-dihydroimidazo[1,2- c ]quinazoline derivative (MF: C 23 H 28 N 8 O 4 ·2HCl; MW: 553.45; CAS Number: 1402152-13-9) [ 127 ].  USRE46856E  (Reissue of US8466283B2) unveils 2,3-dihydroimidazo[1,2- c ]quinazoline derivatives, pharmaceutical compositions comprising them, and the use of these compounds for treating hyperproliferative and angiogenesis disorders. It claims copanlisib and its salts [ 128 ].  US10383876B2  claims copanlisib dihydrochloride salt that possesses technically advantageous properties (stability, solubility, hygroscopicity, etc.) to develop a quality pharmaceutical composition [ 129 ].\nAbemaciclib ( Figure 40 ) is a piperazine-pyridine-pyrimidine based benzimidazole derivative (MF: C 27 H 32 F 2 N 8 ; MW: 506.59; CAS Number: 1231929-97-7) [ 130 ].  US7855211B2  reports piperazine-pyridine-pyrimidine based benzimidazole derivatives and salts thereof, a pharmaceutical formulation comprising them to treat cancers selected from the group colorectal cancer, breast cancer, NSCLC, prostate cancer, glioblastoma, MCL, CML, and AML. It claims abemaciclib and its salts [ 131 ].\nAcalabrutinib ( Figure 41 ) is a pyrrolidine-pyridine based imidazo[1,5- a ]pyrazine derivative (MF: C 26 H 23 N 7 O 2 ; MW: 465.51; CAS Number: 1420477-60-6) [ 132 ].  US9290504B2  provides 4-imidazopyridazin-1-yl-benzamides for the treatment of BTK mediated disorders. It claims acalabrutinib and its salts [ 133 ].  US9796721B2  claims a stable and non-hygroscopic anhydrate crystal form of acalabrutinib as having advantageous parameters for making quality pharmaceutical compositions [ 134 ].\nNetarsudil dimesylate ( Figure 42 ) is an isoquinoline based beta-amino acid derivative (MF: C 30 H 35 N 3 O 9 S 2 ; MW: 645.74; CAS Number: 1422144-42-0) [ 135 ].  US8394826B2  relates to isoquinoline amide and benzamide based compounds as dual inhibitors of Rho kinase and a monoamine transporter (MAT), useful in treating diseases like glaucoma and cancer. It claims netarsudil [ 136 ].  US9415043B2  claims a chemically stable and water-soluble dimesylate salt of netarsudil that can provide a quality ophthalmic solution [ 137 ].\nBaricitinib ( Figure 43 ) is a pyrazole-azetidine based pyrrolo[2,3- d ]pyrimidine derivative (MF: C 16 H 17 N 7 O 2 S; MW: 371.42; CAS Number: 1187594-09-7) [ 138 ].  US8158616B2  provides azetidine derivatives as JAK inhibitors, synthetic methods, and compositions encompassing them to treat inflammatory and autoimmune disorders, along with cancer. It claims baricitinib and its salts [ 139 ].\nBinimetinib ( Figure 44 ) is a benzimidazole derivative (MF: C 17 H 15 BrF 2 N 4 O 3 ; MW: 441.2; CAS Number: 606143-89-9) [ 140 ].  US7777050B2  states alkylated (1H-Benzoimidazol-5-yl)-(4-substituted-phenyl)-amine derivatives, helpful in managing sicknesses like cancer. It claims binimetinib and pharmaceutically acceptable salts thereof [ 141 ].  US9562016B2  claims a crystallized form of binimetinib with better purity and an enhanced physical characteristic, beneficial in pharmaceutical dosage form preparation [ 142 ].\nDacomitinib monohydrate ( Figure 45 ) is a piperidine based quinazolinamine derivatives (MF: C 24 H 25 ClFN 5 O 2 ·H 2 O; MW: 487.95; CAS Number: 1042385-75-0) [ 143 ].  US7772243B2  unveils 4-anilino-6-substituted alkenoylamino-quinazoline compounds as TKIs to treat proliferative diseases, including cancer and restenosis endometriosis and psoriasis. It claims dacomitinib and its salts [ 144 ].\nEncorafenib ( Figure 46 ) is a pyrazole based pyrimidine derivative (MF: C 22 H 27 ClFN 7 O 4 S; MW: 540; CAS Number: 1269440-17-6) [ 145 ].  US8501758B2  provides pyrazole based pyrimidine and pharmaceutical compositions comprising them to treat disorders associated with the deregulated activity of B-Raf. It claims encorafenib and its salts [ 146 ].\nFostamatinib disodium hexahydrate ( Figure 47 ), a phosphate prodrug of tamatinib, is a pyrimidine based pyrido[3,2- b ][1,4]oxazine derivative (MF: C 23 H 24 FN 6 Na 2 O 9 P·6H 2 O; MW: 732.52; CAS Number: 914295-16-2) [ 147 ].  US7449458B2  reports prodrugs of pharmacologically active 2,4-pyrimidinediamine derivatives, intermediates thereof, the process of manufacturing them, and pharmaceutical compositions comprising them to treat diseases mediated by the activation of PTKs. It claims fostamatinib disodium hexahydrate, which has increased solubility concerning the parent phosphate prodrug [ 148 ].  US8163902B2  claims a thermodynamically stable crystalline form of fostamatinib disodium hexahydrate that is stable over a wide range of relative humidity and requires substantial heating to lose its water molecules. This property makes it a suitable API to develop the desired dosage form [ 149 ].\nDuvelisib hydrate ( Figure 48 ) is a purine based isoquinolone derivative (MF: C 22 H 17 ClN 6 O·H 2 O; MW: 434.88; CAS Number: 1201438-56-3) [ 150 ].  US8193182B2  provides isoquinolin-1(2H)-one derivatives as modulators of PI3 kinase activity and pharmaceutical compositions comprising them to treat diseases associated with P13 kinase activity. It claims duvelisib and its salts [ 151 ].  USRE46621E  (Reissue of US8809349B2) claims physically and chemically stable polymorphs of duvelisib, salt, solvate, or hydrate that do not readily decompose or change in chemical makeup or physical state for more than 60 months and are suitable to develop the desired dosage forms of the API [ 152 ].\nGilteritinib fumarate ( Figure 49 ) piperazine-piperidine based pyrazine carboxamide derivative (MF: (C 29 H 44 N 8 O 3 ) 2 ·C 4 H 4 O 4 ; MW: 1221.50; CAS Number: 1254053-84-3) [ 153 ].  US8969336B2  states diamino heterocyclic carboxamide derivatives as having outstanding inhibitory activity against EML4-ALK fusion proteins for use in cancer therapy. It claims gilteritinib and its salts [ 154 ]. The gilteritinib fumarate salt is stable in heat, humidity, and storage conditions.\nLarotrectinib sulfate ( Figure 50 ) is a pyrrolidine based pyrazolo[1,5- a ]pyrimidine derivative (MF: C 21 H 24 F 2 N 6 O 6 S; MW: 526.51; CAS Number: 1223405-08-0) [ 155 ].  US9127013B2  relates to pyrazolo[1,5- a ] pyrimidine derivatives as TRK family PTKIs that are useful to treat cancer, inflammation, and certain infectious diseases. It claims larotrectinib sulfate specifically [ 156 ].  US10172861B2  claims crystalline larotrectinib sulfate having stable physicochemical properties, which can be used to develop quality dosage forms [ 157 ].\nLorlatinib ( Figure 51 ) is a pyrazole-pyridine based benzoxadiazacyclotetradecine derivative (MF: C 21 H 19 FN 6 O 2 ; MW: 406.41; CAS Number: 1223403-58-4) [ 158 ].  US8680111B2  discloses macrocyclic compounds as inhibitors of ALK and/or EML4-ALK and their pharmaceutical composition to treat illnesses linked with the deregulation of ALK and EML4-ALK. It claims lorlatinib and its salts [ 159 ].  US10420749B2  claims crystalline polymorphs of lorlatinib having high crystallinity and purity, low hygroscopicity, and favorable dissolution and mechanical properties to develop quality pharmaceutical formulations [ 160 ].\nEntrectinib ( Figure 52 ) is a tetrahydropyran-piperazine based indazole derivative (MF: C 31 H 34 F 2 N 6 O 2 ; MW: 560.64; CAS Number: 1108743-60-7) [ 161 ].  US8299057B2  discloses indazole derivatives as potent PKIs that are useful in anticancer therapy. It claims entrectinib and its salts [ 162 ].  US10738037B2  claims a crystalline Form 4 of entrectinib that exhibits greater thermodynamic stability at a temperature of about 40 °C than other known polymorphs and offers advantages in preparing dosage forms [ 163 ].\nUpadacitinib hemihydrate ( Figure 53 ) is an imidazo[1,2- a ]pyrrolo[2,3- e ]pyrazine based pyrrolidine derivative (MF: C 17 H 19 F 3 N 6 O·½H 2 O; MW: 389.38; CAS Number: 1310726-60-3) [ 164 ].  USRE47221E  (Reissue of US8426411B2) describes tricyclic compounds that inhibit JAK family kinase activity for treating diseases, including rheumatoid arthritis, multiple sclerosis, and psoriasis. It claims upadacitinib [ 165 ].  US9951080B2  claims physicochemically stable crystalline hemihydrate of upadacitinib having solid-state properties to develop quality pharmaceutical dosage forms [ 166 ].\nAlpelisib ( Figure 54 ) is a pyridine-thiazole based pyrrolidine derivative (MF: C 19 H 22 F 3 N 5 O 2 S; MW: 441.47; CAS Number: 1217486-61-7) [ 167 ].  US8227462B2  unveils pyrrolidine-1,2-dicarboxamide derivatives for the treatment of illnesses ameliorated by inhibition of PI3Ks. It claims alpelisib in a free form and its salts [ 168 ].\nErdafitinib ( Figure 55 ) is a pyrazole based quinoxaline derivative (MF: C 25 H 30 N 6 O 2 ; MW: 446.56; CAS Number: 1346242-81-6) [ 169 ].  US8895601B2  relates to pyrazole based quinoxaline derivatives and their pharmaceutical compositions to treat diseases like cancer. It claims erdafitinib and its salts [ 170 ].\nPexidartinib hydrochloride ( Figure 56 ) is a pyrrolo[2,3- b ]pyridine based pyridine derivative (MF: C 20 H 15 ClF 3 N 5 ·HCl; MW: 454.28; CAS Number: 1029044-16-3) [ 171 ].  US9169250B2  provides fused azacyclic compounds as dual inhibitors of c-FMS and c-KIT to treat diseases that arise due to deregulation of c-FMS and c-KIT. It claims pexidartinib hydrochloride [ 172 ].  US9802932B2  claims a stable crystalline form of pexidartinib hydrochloride having attributes for developing a quality pharmaceutical composition [ 173 ].\nFedratinib dihydrochloride monohydrate ( Figure 57 ) is a pyrrolidine-pyrimidine based benzenesulfonamide derivative (MF: C 27 H 36 N 6 O 3 S·2HCl·H 2 O; MW: 615.62; CAS Number: 1374744-69-0) [ 174 ].  US7528143B2  unveils biaryl m-pyrimidine compounds as an inhibitor of the JAK family and their pharmaceutical compositions to treat diseases mediated by modulation of JAK activity. It claims fedratinib and its salts [ 175 ].\nZanubrutinib ( Figure 58 ) is a piperidine based pyrazolo[1,5- a ]pyrimidine derivative (MF: C 27 H 29 N 5 O 3 ; MW: 471.56; CAS Number: 1691249-45-2) [ 176 ].  US9447106B2  states substituted pyrazolo[1,5- a ]pyrimidines as BTK modulators and used these compounds to treat diseases intervened by BTK. It claims zanubrutinibas and its salts [ 177 ].\nAvapritinib ( Figure 59 ) is a pyrazole-piperazine-pyrimidine based pyrrolo[2,1- f ][1,2,4]triazine derivative (MF: C 26 H 27 FN 10 ; MW: 498.57; CAS Number: 1703793-34-3) [ 178 ].  US9944651B2  refers to piperazine-based pyrrolo[2,1- f ][1,2,4]triazine derivatives for treating conditions like mastocytosis and mast cell diseases by modifying the activity of KIT. It claims avapritinib and its salts [ 179 ].\nSelumetinib sulfate ( Figure 60 ) is a benzimidazole derivative (MF: C 17 H 17 BrClFN 4 O 7 S; MW: 555.76; CAS Number: 943332-08-9) [ 180 ].  US7425637B2  reports  N 3-alkylated benzimidazole compounds that inhibit MEK and are helpful to treat cancer and inflammation. It claims selumetinib and its salts [ 181 ].  US9156795B2  claims a stable crystalline hydrogen sulfate salt of selumetinib with enhanced solubility and bioavailability, making it a suitable API to develop desired pharmaceutical dosage forms [ 182 ].\nPemigatinib ( Figure 61 ) is a morpholine based pyrrolo[3′,2′:5,6]pyrido[4,3- d ]pyrimidine derivative (MF: C 24 H 27 F 2 N 5 O 4 ; MW: 487.5; CAS Number: 1513857-77-6) [ 183 ].  US9611267B2  relates to tricyclic compounds as inhibitors of FGFR, useful in ailments facilitated by FGFR malfunctioning like cancer. It claims pemigatinib and its salts [ 184 ].\nTucatinib ( Figure 62 ) is a quinazoline-oxazoline based triazolo[1,5- a ]pyridine derivative (MF: C 26 H 24 N 8 O 2 ; MW: 480.52; CAS Number: 937263-43-9) [ 185 ].  US8648087B2  discloses  N 4-phenyl-quinazoline-4-amine derivatives as TKIs to treat cancer and inflammation. It claims tucatinib [ 186 ].\nCapmatinib dihydrochloride monohydrate ( Figure 63 ) is an imidazo[1,2- b ][1,2,4]triazine based quinoline derivative (MF: C 23 H 21 Cl 2 FN 6 O 2 ; MW: 503.36; CAS Number: 1865733-40-9) [ 187 ].  US7767675B2  reveals imidazotriazines and imidazopyrimidines as MET inhibitors and their pharmaceutical compositions useful in cancer treatment. It claims capmatinib and its salts [ 188 ].  US8420645B2  claims a stable capmatinib dihydrochloride monohydrate with pharmaceutical attributes to manufacture quality pharmaceutical formulations [ 189 ].\nSelpercatinib ( Figure 64 ) is a pyridine-diazabicycloheptane based pyrazolo[1,5- a ]pyridine derivative (MF: C 29 H 31 N 7 O 3 ; MW: 525.61; CAS Number: 2152628-33-4) [ 190 ].  US10112942B2  uncovers pyrazolo[1,5- a ]pyridines as RET inhibitors, useful to treat RET-associated diseases. It claims selpercatinib and its salts [ 191 ].  US10584124B2  claims a stable crystalline polymorph of selpercatinib that is useful for developing pharmaceutical formulations [ 192 ].\nRipretinib ( Figure 65 ) is a naphthyridine based phenylurea derivative (MF: C 24 H 21 BrFN 5 O 2 ; MW: 510.36; CAS Number: 1442472-39-0) [ 193 ].  US8461179B1  uncovers dihydronaphthyridine derivatives that inhibit c-KIT and that have utility to treat GIST, mast cell leukemia, or mastocytosis. It claims ripretinib and its salts [ 194 ].\nPralsetinib ( Figure 66 ) is a pyridine-pyrimidine based pyrazole derivative (MF: C 27 H 32 FN 9 O 2 ; MW: 533.61; CAS Number: 2097132-94-8) [ 195 ].  US10030005B2  discloses pyrazole based RET inhibitors and their pharmaceutical compositions to treat a condition mediated by aberrant RET activity, e.g., cancer. It claims pralsetinib [ 196 ].\nTrilaciclib dihydrochloride ( Figure 67 ) is a piperazine-pyridine based pyrazino[1′,2′:1,5]pyrrole derivative (MF: C 24 H 30 N 8 O·2HCl; MW: 519.48; CAS Number: 1977495-97-8) [ 197 ].  US8598186B2  reveals tricyclic compounds as CDK inhibitors, which have utility in the treatment of disorders intervened by CDK malfunction like cancer. It claims trilaciclib and its salts [ 198 ].\nTepotinib hydrochloride monohydrate ( Figure 68 ) is a piperidine-pyrimidine based dihydropyridazine derivative (MF: C 29 H 28 N 6 O 2 ·HCl·H 2 O; MW: 547.05; CAS Number: 1946826-82-9) [ 199 ].  US8580781B2  reveals certain pyridazinones as MET inhibitors to treat tumors. It claims tepotinibor and its salts [ 200 ]. Tepotinib hydrochloride hydrate is claimed explicitly in  US8329692B2  [ 201 ].\nUmbralisibtosylate ( Figure 69 ) is a chromen-4-one based pyrazolo[3,4- d ]pyrimidine derivative (MF: C 38 H 32 F 3 N 5 O 6 S; 743.75; 1532533-72-4) [ 202 ].  US10570142B2  provides pyrazolo[3,4- d ]pyrimidines as inhibitors of PI3K δ  and their pharmaceutical compositions to treat PI3K δ  mediated disorders. It claims umbralisib tosylate having at least 95% enantiomeric excess [ 203 ].  US10414773B2  unveils a stable crystalline form of umbralisib tosylate possessing specified particle sizes with enhanced solubility and improved pharmacokinetics. This property makes it suitable to prepare a quality oral dosage form [ 204 ].\nTivozanib hydrochloride monohydrate ( Figure 70 ) is an isoxazole base quinoline derivative (MF: C 22 H 19 ClN 4 O 5 ·HCl·H 2 O; MW: 509.34; CAS Number: 682745-41-1) [ 205 ].  US6821987B2  and  US7211587B2  unveil quinoline derivatives having azolyl group, useful for treating tumors, chronic rheumatism, psoriasis, and Kaposi’s sarcoma. These patents claim tivozanib and its salts [ 206 , 207 ].  US7166722B2  claims a physically stable crystalline form of tivozanib hydrochloride monohydrate stable under high temperature and humidity. This form is suitable for developing quality dosage forms [ 208 ].\nInfigratinib ( Figure 71 ) is a piperazine based pyrimidine derivative (MF: C 26 H 31 Cl 2 N 7 O 3 . H 3 PO 4 ; MW: 658.47; CAS Number: 1310746-10-1) [ 209 ].  US8552002B2  claims infigratinib and its salts [ 210 ].  US9067896B2  claims a monophosphoric acid salt of infigratinib as well as its anhydrous crystalline polymorph (Form A) and amorphous polymorph. The stability and physicochemical parameters of the crystalline Form A were better than other disclosed polymorphs [ 211 ].\n\nIn 2001, USFDA approved the marketing of the first clinical PKI, imatinib. From 2001 to 31 May 2021, about 70 PKIs have been approved by the USFDA ( Table 2 ). The USFDA has also approved antibodies as PKIs such as trastuzumab and bevacizumab. A few antibodies are also in the clinical trial (amivantamab and patritumab). This review is limited to small molecules as PKIs. Accordingly, USFDA approved antibodies such as PKIs have not been discussed here. The physicochemical properties of about 55 USFDA approved PKIs from 2001 to 2020 have been described in the literature [ 22 , 23 ]. However, these reports are silent about the patent data of the PKIs reported therein.\nAccording to the patent literature, and the data presented in  Table 2  and  Table 3 , the major players that developed the marketed PKIs include Novartis (imatinib, lapatinib, everolimus, nilotinib, pazopanib, trametinib, dabrafenib, ceritinib, ribociclib, midostaurin, alpelisib, capmatinib, and infigratinib), Pfizer (tofacitinib, palbociclib, dacomitinib, and lorlatinib), Astrazeneca (gefitinib, osimertinib, acalabrutinib, and selumetinib), Bayers (sorafenib, regorafenib, copanlisib, and larotrectinib), and PF Prism (temsirolimus, crizotinib, axitinib, and bosutinib). Nearly 535 PKs have been reported [ 6 ]. However, the major primary target of the approved PKIs includes ALK, BCR-Abel, B-RAF, BTK, CDK, EGFR, JAK, MEK, PDGFR, PI3K, RET, and VEGFR ( Table 2 ). Accordingly, there remains a large number of unexplored PKs. Some KIs have specificity for multiple kinases and are called multikinase inhibitors (MKIs), such as sunitinib, regorafenib, imatinib, sorafenib, axitinib, lenvatinib, cabozantinib, vandetanib, and pazopanib. The MKIs are supposed to reduce the chances of developing resistance. However, they are also linked to causing adverse effects in patients, for example, hypertension, gastric upset, and dermatological reactions [ 212 ]. The development of the covalent PKIs (ibrutinib, dacomitinib, osimertinib, afatinib, and neratinib) had been an unwilling strategy because they can bind to certain proteins and cause toxicity. Furthermore, the allosteric PKIs (trametinib, ascinimib, and selumetinib) are considered better than covalent inhibitors as they are not supposed to bind with other proteins. However, many new kinases have been identified possessing cysteine residues at their active sites. Therefore, the design of potent and selective covalent inhibitors may be useful against such kinases [ 213 , 214 ]. The pharmaceutical industries are trying to develop more potent and safer PKIs that can be used to treat many more PKs associated disorders with fewer adverse events [ 23 ]. Some example of PKIs, which are under development and/or waiting for the USFDA approval, include abrocitinib, belumosudil, dovitinib, sitravatinib, abivertinib, enzastaurin, rivoceranib (apatinib), asciminib, ensartinib, mobocertinib, momelotinib, pacritinib, quizartinib, vorolanib, GLPG3970, CA-4948, BAY1834845, BAY1830839, and PF-06650833 [ 213 , 214 ].\nThe PKIs contain one or more heterocyclic moieties in their structure that can explain the difference in their binding to the target and thus the spectrum of activity. The primary heterocyclic moieties include quinazoline, quinoline, isoquinoline, pyridine, pyrimidine, pyrazole, benzimidazole, indazole, imidazole, indole, carbazole, or their fused structures. This observation suggests that many clinical PKIs have been developed by the chemical modification of a formerly approved drug, and PKs are promiscuous targets. Further, most of the PKIs are marketed as acid-addition salts (hydrochloride, mesylate, tosylate, phosphate, malate, citrate, esylate, fumarate, succinate, and sulfate). This observation indicates the basic nature of the chemical nucleus of the PKIs.\nThe majority of the PKIs are approved to treat cancer and inflammatory disorders. Some of the PKIs have shown efficacy towards autoimmune diseases, Alzheimer’s disease (neflamapimod, tideglusib, and saracitinib), and Parkinson’s disease (DNL201). It is also expected that PKIs of PKC/WNK that control the activity of ion transporters may be developed to treat hypertension [ 214 ].\nThe malignant cells have genomic instability, which may cause the development of resistance to PKIs. This phenomenon is the reason for developing 2nd, 3rd, and later generations of PKIs targeting the equivalent PKs and their related disorders [ 212 ]. To combat resistance development, scientists are exploring different chemical templates and pharmacophores to develop novel PKIs [ 22 ]. Besides, inflammatory conditions do not exhibit genomic instability. Therefore, the PKIs, which are approved to treat inflammatory disorders, seldom demonstrate the development of resistance [ 22 , 23 ].\nThe main marketed dosage form of about 66 USFDA approved PKIs is either a tablet or capsule ( Table 2 ). These are solid dosage forms. The quality of the formulation of a solid dosage form depends upon the solid-state properties (stability, solubility, compressibility, etc.) of the drug [ 215 ]. Therefore, many patents related to salts and polymorphs (mostly crystalline forms) of the USFDA approved PKIs have been obtained by the innovator companies. The innovator companies have done this to capture the market for a longer time.\nThe development of the PKIs is considered a medical breakthrough. However, the prices of these therapeutics cause financial toxicity. The financial burden can make the patients non-compliant with the treatment instructions as they may take lower doses than the prescribed doses. This causes failure of the treatment [ 216 , 217 ]. One way to avoid financial toxicity is to develop the generic version of a drug [ 218 ]. Currently, seven PKIs have been genericized (imatinib, erlotinib, sorafenib, dasatinib, lapatinib, temsirolimus, and everolimus) ( Table 3 ). These generic versions must have lower prices than the innovator products. The data given in  Table 3  also suggest that twelve more PKIs (gefitinib, sunitinib, pazopanib, vandetanib, axitinib, bosutinib, tofacitinib, idelalisib, nintedanib, lenvatinib, midostaurin, and neratinib) may be genericized by 2025 due to basic/compound/governing patent expiry or expiry of the drug exclusivity. It means by the end of 2025, 19 PKIs will have their generic version in the USA market. Besides, it is also expected that the generic version of about 48 PKIs will be available in the USA market by the end of 2030. Thus, it is hoped that the generic availability of these PKIs will reduce the financial toxicity on a patient.\nAlthough great strides have been made in developing small molecule such as PKIs during the past 20 years, this field is still in its infancy. PKs are ubiquitous, and hence specificity has always been an issue regarding the design of new therapies targeting them. The major disadvantage of the existing PKIs is that they target a minor portion of the kinome, with countless clinically significant kinases missing validated inhibitors [ 22 , 23 ]. There are essential kinases without any inhibitors, and this is a critical area for further research. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed. Other innovative strategies are also expected soon. A summary of the PKIs is provided in  Figure 72 .\nIn conclusion, there is a huge scope for discovering PKIs, and it will dominate other cancer discovery strategies for decades. The rate of discovery of better and selective PKIs having less propensity for resistance development will be faster than the last two decades because of the better understanding of the molecular and structural aspects of the human kinases. The development of PKIs to treat hypertension, Alzheimer’s disease, and Parkinson’s disease are foreseeable.","source_license":"CC-BY-4.0","license_restricted":false}